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Review

Therapeutic Effects of Pharmacological Modulation of Serotonin Brain System in Human Patients and Animal Models of Fragile X Syndrome

by
Lucia Ciranna
1,* and
Lara Costa
2
1
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
2
Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(6), 2495; https://doi.org/10.3390/ijms26062495
Submission received: 4 February 2025 / Revised: 5 March 2025 / Accepted: 7 March 2025 / Published: 11 March 2025
(This article belongs to the Special Issue Current Molecular Science of Fragile X Syndrome and Associated Disorders)
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Abstract

:
The brain serotonin (5-HT) system modulates glutamatergic and GABAergic transmission in almost every brain area, crucially regulating mood, food intake, body temperature, pain, hormone secretion, learning and memory. Previous studies suggest a disruption of the brain 5-HT system in Fragile X Syndrome, with abnormal activity of the 5-HT transporter leading to altered 5-HT brain levels. We provide an update on therapeutic effects exerted by drugs modulating serotonergic transmission on Fragile X patients and animal models. The enhancement of serotonergic transmission using Selective Serotonin Reuptake Inhibitors (SSRIs) corrected mood disorders and language deficits in Fragile X patients. In Fmr1 KO mice, a model of Fragile X Syndrome, selective 5-HT7 receptor agonists rescued synaptic plasticity, memory and stereotyped behavior. In addition, drugs specifically acting on 5-HT1A, 5-HT2 and 5-HT5 receptor subtypes were able to correct, respectively, epilepsy, learning deficits and hyperactivity in different Fragile X animal models. In conclusion, the SSRI treatment of Fragile X patients improves mood and language; in parallel, studies on animal models suggest that compounds selectively acting on distinct 5-HT receptor subtypes might provide a targeted correction of other Fragile X phenotypes, and thus should be further tested in clinical trials for future therapy.

1. Introduction

1.1. Physiological Role of Serotonin

Serotonin (5-HT) is a neurotransmitter and neuromodulator widely distributed in the central nervous system and in peripheral tissues, particularly in the gut and in blood platelets. In the brain, 5-HT is produced by neurons located in raphe nuclei and projected to cortical areas, limbic structures, the hippocampus, the hypothalamus, the cerebellum and the spinal cord, by which 5-HT regulates mood, cognition, hormone production, food intake, body temperature, the sleep–wake cycle and pain transmission [1]. In addition, 5-HT plays a crucial role in neurite outgrowth and synapse formation during brain development [2], and a disruption of 5-HT transmission at early developmental stages is a recognized cause of autism [1,3]. 5-HT exerts its effects on target neurons by the activation of many different subtypes of receptors, grouped into seven families, from 5-HT1 to5-HT7 [4].

1.2. Serotonin Receptors

Almost all 5-HT receptors are G-protein-coupled metabotropic receptors, with the exception of the 5-HT3 type, which belongs to the superfamily of ligand-gated ion channels. 5-HT1 receptors are negatively coupled to adenylate cyclase and include five subtypes named 5-HT1A, 5-HT1B, 5-HT1D, 5-ht1E and 5-HT1F (lower case appellations were attributed to 5-HT receptors that were cloned but not identified in native tissues). 5-HT1A receptors are widely distributed in the brain, particularly in limbic areas and in the hippocampus; in raphe nuclei they are expressed on the soma and dendrites of serotonergic neurons, where they function as autoreceptors, inhibiting cell firing and 5-HT release in target brain areas. The 5-HT1B and 5-HT1D receptors are highly expressed in basal ganglia; these receptors also exert vascular effects and are the target of sumatryptan and related antimigraine drugs. The subtype initially named 5-HT1C was later found to be coupled to phosphoinositide signaling, and was thus renamed 5-HT2C and included in the 5-HT2 receptor family.
The 5-HT2 receptors include 5-HT2A, 5-HT2B and 5-HT2C subtypes, which are coupled to Gq and stimulate phospholipase C, inositol 3-phosphate signaling and intracellular calcium release [4]. 5-HT2A receptors are highly expressed in the cerebral cortex, in the olfactory bulb and in many brainstem nuclei (motor trigeminal, facial and hypoglossal); intermediate levels were found in limbic areas and in basal ganglia, and they have very little expression in the hippocampus and no expression in the cerebellum and thalamus. In the brain, 5-HT2A receptor activation induces depolarizing effects, whereas in peripheral tissues they stimulate smooth muscle contraction. 5-HT2B receptors are expressed in many peripheral tissues; their brain expression is strictly limited to the cerebellum, lateral septum, hypothalamus and amygdala, and they seem to play a role in anxiety. 5-HT2C receptors (initially identified in the choroid plexus and named 5-HT1C) are expressed in the hippocampus, in limbic structures, in some thalamic nuclei and in the basal ganglia of rodents, and their malfunction might be involved in affective disorders.
5-HT3 receptors (including two subtypes, 5-HT3A and 5-HT3B) are ligand-gated cation channels mediating fast depolarization; they are located on neurons of the dorsal vagal complex responsible for the vomiting reflex, which accounts for the antiemetic action of 5-HT3 receptor antagonists [4]. In addition, 5-HT3 receptors are expressed in mouse and rat hippocampus GABAergic interneurons and play a role in synaptic plasticity [5,6].
5-HT4 receptors were identified in mouse colliculi neurons and in guinea pig brains for their ability to stimulate adenylate cyclase activity and cyclic adenosine monophosphate (cAMP) production [7,8]. They are expressed in peripheral tissues, including the heart and the intestines, and in several brain regions, particularly in the limbic system, hippocampus and brain cortex. Several studies show that the activation of 5-HT4 receptors exerts pro-cognitive effects; thus, these receptors have become a target in cognition deficits [9,10].
5-HT5 receptors were cloned in 1994, but their expression in native tissues remained uncertain until recently and their identification was difficult due to the lack of selective ligands. Two receptor subtypes, 5-HT5A and 5-HT5B, have been identified in mice and rats, whereas in the human brain only the 5-HT5A subtype is expressed. Their predominant signaling mechanism is the inhibition of adenylate cyclase activity through Gi/o proteins. Interestingly, 5-HT5 receptors are selectively expressed in the brain, particularly in the hippocampus and frontal cortex; their physiological role, still to be clarified, seems to be related to the control of the circadian rhythm, mood and learning [11].
5-HT6 receptors, similar to 5-HT5, are brain-specific: they have been localized in rat and human striatum, amygdala, hippocampus, cortex and olfactory tubercle. 5-HT6 receptors stimulate adenylate cyclase activity; they modulate cholinergic and monoaminergic transmission, and their physiological function, still to be clarified, is related to mood and learning [4,12].
5-HT7 receptors were cloned in 1993 by three distinct laboratories [13,14,15]. In rat and mouse brains, 5-HT7 receptors are highly expressed in the thalamus, hypothalamus and hippocampus, with lower amounts in the cerebral cortex, amygdala, striatum, cerebellum and spinal cord (reviewed by [16]). In the human brain, 5-HT7 receptors were found in the same brain areas as in rat and mouse models, with high expression levels in the thalamus, dorsal raphe, hippocampus and hypothalamus [17,18]. In addition, the human brain contains high levels of 5-HT7 receptors in the caudate nucleus, putamen and substantia nigra [17]. 5-HT7 receptors are metabotropic receptors coupled to Gs, and they induce adenylate cyclase stimulation, cAMP formation and the activation of several kinases, including protein kinase A (PKA) [13,15,19], extracellular signal-regulated kinase (ERK) [20,21,22] and the kinase Akt (also known as protein kinase B) [23,24]. Interestingly, 5-HT7 receptors are also linked to G12 [25], a heterotrimeric G-protein-modulating “small” monomeric GTPases [26]. Through the G12-dependent activation of the small GTPases RhoA and Cdc42, 5-HT7 receptor activation regulates gene transcription, neuronal morphology, neuronal excitability and synaptic plasticity [25,27,28]. 5-HT7 receptors play a crucial role in neurite and dendrite outgrowth during development [28,29], control sleep and thermoregulation [27] and exert pro-cognitive effects [30,31,32]. In our laboratory, we found that 5-HT7 receptors modulate synaptic transmission and plasticity in the hippocampus of wild-type mice and rescue defects in synaptic plasticity, learning and behavior in Fmr1 KO mice, a model of Fragile X Syndrome, and are thus a promising target for the future therapy of this disease (see below).

1.3. Fragile X Syndrome

Fragile X Syndrome is a genetic form of intellectual disability affecting 1/4000 males and 1/8000 females, caused by the silencing of the FMR1 gene, located on the X chromosome, coding for Fragile X Messenger Ribonucleoprotein Protein (FMRP) [33,34]. FMRP is an mRNA-binding protein rapidly produced in neuronal dendrites following the activation of metabotropic glutamate receptors (mGluRs) [35], and plays a crucial role as a translation modulator of a large number of synaptic proteins [36,37]. In Fragile X Syndrome, the silencing of the FMR1 gene leads to the reduced or absent production of FMRP, causing a disruption of synaptic structure and function: abnormally long, thin and immature dendritic spines have been observed in the brain cortex of Fragile X patients [38] and of Fmr1 gene knockout (Fmr1 KO) mice, a model of this disease [39]. Electrophysiology studies on Fmr1 KO mice hippocampi first identified a peculiar alteration of synaptic plasticity: in particular, long-term depression induced by metabotropic glutamate receptors (mGluR-LTD) was abnormally enhanced [40], leading to the “mGluR theory” of Fragile X Syndrome [41]. In addition, several alterations of synaptic transmission were later discovered, including disrupted mGluR coupling to intracellular signaling [42], altered cell-surface receptor mobility and a lack of mGluR-LTD or NMDA-mediated synaptic currents [43], a reduced NMDA/AMPA ratio [43,44,45], altered NMDA-dependent plasticity [46,47] and reduced GABAergic inhibitory transmission [48,49,50,51].
Defects in synaptic transmission and plasticity in turn impair learning, memory, mood and behavior, both in human Fragile X patients [52] and in animal models of the disease [53]. The most serious Fragile X symptoms (with variable severity in different patients) include cognitive deficits, epilepsy, attention deficit and hyperactivity disorder, anxiety and autistic behavior [52]. Since mood and cognition are crucially regulated by 5-HT in physiological conditions, the modulation of serotonergic transmission might improve impaired learning and behavioral functions in Fragile X Syndrome. In the following paragraphs, we will review the literature showing that 5-HT brain functions are probably altered in Fragile X Syndrome and that the pharmacological modulation of 5-HT neurotransmission can correct many symptoms of the disease.

2. Serotonin Dysregulation in Fragile X Patients and Therapeutic Effects of Selective Serotonin Reuptake Inhibitors

Brain 5-HT levels and the amount of expression of 5-HT receptors have not been measured in Fragile X patients. A dysregulation of the brain 5-HT system during development is well known in non-syndromic forms of autism, and thus might also occur in Fragile X Syndrome [54].
In young Fragile X patients, polymorphisms on the 5-HT transporter (5-HTT or SERT) gene were found to be highly related to aggressive and autistic behavior. In particular, Fragile X patients showing the highest level of aggressive, self-injuring and repetitive behavior were homozygous for a high-transcribing long form of the gene, leading to an enhanced expression of 5-HTT and a higher re-uptake of serotonin. On the other side, patients homozygous for a short genotype, with a lower expression of 5-HTT and a less efficient serotonin re-uptake, showed the lowest levels of aggressive and self-destructive behavior [55].
A very recent work shows reduced 5-HT levels in the striatum of young adult Fmr1 KO mice [56]. In Fmr1 KO mice of early post-natal age, the expression level of the mRNA for 5-HTT (also named SERT) was reduced in their thalamic nuclei, suggesting that 5-HT levels were altered; this might account for the plasticity defects of Fmr1 KO mice during the critical period of development [57]. Another work shows that, in physiological conditions, FMRP interacts with 5-HTT, suggesting that in Fragile X Syndrome the lack of FMRP alters 5-HTT expression and/or activity [58].
Selective Serotonin Reuptake Inhibitors (SSRIs), enhancing 5-HT levels in the synaptic cleft, are very effective antidepressant and anti-anxiety drugs, and are often prescribed to Fragile X patients to reduce anxiety and depression [54]. In addition to mood disorders, SSRIs also correct other symptoms (Table 1): a case report on a very young Fragile X patient (3 years old) with a delay in language development showed a significant improvement of speech ability, described as an “explosion of verbalization”, following treatment with sertraline, an SSRI [59]. This observation was later confirmed by a clinical trial on very young children (2 to 6 years old) with Fragile X Syndrome, in which 6 months of treatment with a low dose of sertraline improved language expression, particularly in children with concomitant autistic features. Sertraline treatment also improved the visual perception and fine motor skills of children with Fragile X [60]. An improvement in language expression by SSRI treatment was observed specifically in Fragile X patients and not in non-syndromic autistic patients [61].
Some variability in the responsiveness of different Fragile X patients to SSRIs was found to be related to polymorphisms in genes involved in serotonergic transmission, including the 5-HTT gene [62].
Taken together, all these studies indicate that enhancing brain serotonergic transmission by SSRI treatment improves the mood and language of Fragile X patients, particularly when treatment is started at a young age during the critical period of brain development.
Table 1. Effects of drugs modulating serotonergic transmission in Fragile X patients and animal models.
Table 1. Effects of drugs modulating serotonergic transmission in Fragile X patients and animal models.
Pharmacological CategoryDrugExperimental ModelEffectsReferences
Selective Serotonin Reuptake Inhibitor (SSRI)Sertraline (2.5 mg/day)
Sertraline (20 mg/day)		Fragile X patients, one boy (3 years old)
one girl (7 years old).		Improvement of speech ability.
Reduced anxiety		[59]
SSRISertraline (2.5–5 mg/day)Fragile X patients (2–6 years old, 48 males and 9 females).Improvement of language, visual perception and fine motor skills.[60]
5-HT1A agonistFPT (mixed agonist of 5-HT1, 5-HT2C and 5-HT7 receptors), 5.6 mg/kg.Fmr1 KO mice, (males and females)Prevention of audiogenic seizures; increase of social interaction; anxiolytic effects.[63]
5-HT1A agonistFPT (5.6 mg/kg)Fmr1 KO mice
(males and females)		Rescue of electroencephalogram activity[64]
5-HT1A agonistNLX-101 (1.2–2.4 mg/Kg)Fmr1 KO mice
(males and females)		Reduction of audiogenic seizures[65]
5-HT1A agonistNLX-112 (1.0–2.5 mg/Kg)Fmr1 KO mice
(males and females)		Prevention of audiogenic seizures[66]
5-HT1A agonistEltoprazine (1 mM for 30 min)FXS Drosophila model
(sex not indicated)		Rescue of abnormal mitochondrial function; rescue of locomotor activity[67]
5-HT2A antagonistMDL11939 (1 μM for electrophysiology; 1 mg/Kg for behavioral tests)Fmr1 KO mice (males and females)Rescue of synaptic plasticity (GluA1 synaptic delivery); partial rescue of learning deficits[68]
5-HT2B agonistBW723C86 (1 μM for electrophysiology; 5 mg/Kg for behavioral tests)Fmr1 KO mice (males and females)Rescue of synaptic plasticity (GluA1 synaptic delivery); partial rescue of learning deficits[68]
5-HT5A antagonistASP5736 (0.01–0.1 mg/kg)Fmr1 KO rats (males)Correction of hyperactivity, abnormal sensory motor gating and learning deficits[69]
5-HT7 agonist5-HT (10 μM); 8-OH-DPAT (100 nM); LP-211 (10 nM); BA-10 (10 nM)Fmr1 KO mice (males and females)Rescue of synaptic plasticity (mGluR-LTD)[70,71]
5-HT7 agonistLP-211 (10 nM)Fmr1 KO mice (males and females)Rescue of synaptic plasticity, learning and stereotyped behavior.[72]
5-HT7 agonistLP-211 (3 mg/Kg)Fmr1 KO mice (males)Rescue of stereotyped behavior[73]

3. Selective Agonists of 5-HT7 Receptors Rescued Synaptic Plasticity, Learning Deficits and Autistic Behavior in Fmr1 KO Mice

As above mentioned, 5-HT7 receptors are expressed in human brain areas involved in learning, particularly in the thalamus, hypothalamus, amygdala and hippocampus [74], and several reports show that 5-HT7 receptor activation exerts pro-cognitive effects in experimental animal models [32]. In our laboratory, we initially observed the short-term effects of two distinct 5-HT receptors on basal glutamatergic transmission in the hippocampus of wild-type mice: AMPA receptor-mediated synaptic transmission was reduced by the activation of 5-HT1A receptors by a pre-synaptic mechanism, and was enhanced at a post-synaptic level by the activation of 5-HT7 receptors [75]. Therefore, we decided to study the effects of 5-HT receptors in Fmr1 KO mouse hippocampi, in which long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD) is exaggerated due to the excessive removal of AMPA receptors [40]. We found that the activation of 5-HT7 receptors reversed hippocampal mGluR-LTD in both wild-type and Fmr1 KO mice, in which this form of plasticity is abnormally enhanced: the brief application (5 min) of a 5-HT7 receptor agonist exerted a long-lasting reversal of mGluR-LTD that was still observed over 45 min after LTD induction (Figure 1A and Table 1). This effect of 5-HT7 receptors was exerted at a post-synaptic level by preventing the mGluR-induced membrane removal of AMPA receptors [70]. The reversal of mGluR-LTD by 5-HT7 receptors was mediated by adenylate cyclase activation and protein kinase A stimulation (Figure 1A) [72]. This result is in line with the “cAMP theory of Fragile X Syndrome”, which is based on several observations: cAMP production is reduced in the blood platelets of Fragile X patients [76,77], in the brain of drosophila and mouse Fragile X models and in neural precursor cells from human Fragile X fetal tissues [78]; phosphodiesterase 2a (an enzyme breaking down cAMP) is one of the main targets of physiological FMRP inhibitory control [79], and is thus overactive in Fmr1 KO mouse neurons, leading to reduced cAMP levels [80].
We found that the 5-HT7 receptor-mediated reversal of mGluR-LTD also involved activation of cyclin-dependent kinase 5 (Cdk5; Figure 1A) [81], a kinase that plays a physiological role in brain development and function [82] and is disrupted in several disorders of the central nervous system [83]. Interestingly, Cdk5 expression was found to be reduced in the hippocampus of Fmr1 KO mice [84]. Cdk5 downregulation has also been associated with epilepsy [85] and attention deficit and hyperactivity disorder (ADHD) [86], both frequent symptoms in Fragile X patients. Concerning the 5-HT7 receptor-mediated rescue of mGluR-LTD that we described in Fmr1 KO mice, the relationship between cAMP formation and Cdk5 activation by 5-HT7 receptors needs to be clarified.
Finally, the in vivo administration of LP-211, a selective 5-HT7 receptor agonist with drug-like properties [87], rescued object recognition memory and reduced stereotyped marble burying behavior in Fmr1 KO mice (Figure 1B) [72]. Accordingly, the administration of LP-211 reduced repetitive self-grooming behavior in Fmr1 KO mice [73]. These data together suggest that 5-HT7 receptor agonists might be further studied in view of clinical studies on Fragile X patients with cognitive impairment and autistic behavior.

4. Drugs Acting on Distinct 5-HT2 Receptor Subtypes Rescued Synaptic Plasticity and Learning in Fmr1 KO Mice

The activation of 5-HT2 receptors was found to inhibit NMDA-receptor-induced LTP in wild-type rat visual cortex by a mechanism involving phospholipase C signaling and GABAergic interneurons; the subtype of 5-HT2 receptors was not identified [88]. Later work investigated the effects of distinct 5-HT2 receptor subtypes (5-HT2A, 5-HT2B and 5-HT2C) on NMDA-receptor-mediated synaptic plasticity in wild-type and Fmr1 KO mice. In mouse anterior cingulate cortex (a limbic brain area involved in attention, reward, decision-making and emotions), the inhibition of 5-HT2A receptors enhanced NMDA-receptor-induced LTP in wild-type animals but not in Fmr1 KO mice, in which LTP had a small amplitude and was not potentiated by 5-HT2A antagonists. The effect of 5-HT2A antagonists in wild-type mice relied on a post-synaptic mechanism; since the expression level of 5-HT2 receptors in the anterior cingulate cortex of Fmr1 KO mice was not modified with respect to wild-type mice, the authors suggest a disruption of receptor functioning [89]. Another work instead shows that in Fmr1 KO mice, a 5-HT2A receptor antagonist rescued alterations in the membrane trafficking of GluA1 AMPA receptor subunits and LTP defects in the hippocampus and brain cortex, as well as learning deficits evaluated by the fear conditioning protocol and Y maze test [68]. No rescue effect was observed after the selective modulation of 5-HT2C receptors, nor when all 5-HT2 receptor subtypes were activated by a non-selective 5-HT2 receptor agonist. The same work shows that a recovery of synaptic plasticity and learning in Fmr1 KO mice was observed after the application of either a 5-HT2A receptor antagonist or a 5-HT2B receptor agonist, a D1 receptor agonist and a D2 receptor antagonist; interestingly, a combination of 5-HT and DA agonists and antagonists at very low doses synergistically rescued synaptic plasticity and learning, suggesting that therapy with a drug cocktail at low doses might be effective, while reducing adverse effects.
These data (Table 1) indicate that either the blockade of 5-HT2A receptors or activation of 5-HT2B receptors corrects reduced LTP and learning deficits in Fmr1 KO mice.

5. Activation of 5-HT1A Receptors Corrected Abnormal Phenotypes in Mouse and Drosophila Models of Fragile X Syndrome

In addition to 5-HT2A receptors, 5-HT1A receptors also inhibited NMDA-mediated synaptic responses and LTP in rat primary visual cortexes [90,91]. The effects of 5-HT1A receptors on LTP have not been tested in Fmr1 KO mice; it would be interesting to check if the blockade of 5-HT1A receptors might rescue the reduced LTP in Fmr1 KO mice.
On the other side, the activation (rather than blockade) of 5-HT1A receptors is able to prevent seizures and rescue behavior in Fmr1 KO mice (Table 1). The aminotetralin (S)-5-(2′-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT), a partial agonist of the 5-HT1A, 5-HT2C and 5-HT7 receptors and a full agonist of the 5-HT1B, and 5-HT1D receptors, reduced repetitive behaviors and increased social attitude in wild-type mice [92]. In Fmr1 KO mice, the in vivo administration of FPT completely prevented audiogenic seizures, exerted anxiolytic effects and increased social interactions [63]. Accordingly, the in vivo administration of NLX-101, a selective 5-HT1A-biased agonist, reduced audiogenic seizures in Fmr1 KO mice; the authors made the hypothesis that 5-HT1A receptors located in the inferior colliculus inhibit hyperactive neurons responsible for auditory hypersensitivity and generating audiogenic seizures [65].
In Fmr1 KO mice, similar to Fragile X patients, neuronal hyperexcitability is also present in the somatosensory and auditory brain cortexes, and can be evidenced by altered electroencephalogram activity, with an abnormal increase in gamma waves (30–80 Hz) being seen. The in vivo administration of FPT corrected abnormal electroencephalogram activity in the somatosensory cortex and exerted different sex-specific effects in the auditory cortex of adult Fmr1 KO mice [64].
In line with the above cited results, a reduced 5-HT1A receptor expression was recently described in the brain of juvenile (not adult) Fmr1 KO mice at the age of highest seizure susceptibility: at this age, the administration of NLX-112, a selective 5-HT1A receptor agonist, effectively prevented seizures [66]. The authors also suggested that antiepileptic treatment with a 5-HT1A receptor agonist should be started in young Fragile X patients.
A very recent study shows that a drosophila model of Fragile X Syndrome displayed an abnormally increased number of mitochondria and oxidative hyperactivity in the neurons of the neuromuscular junction, together with a reduced locomotor activity; these malfunctions were corrected by treatment with eltoprazine, a selective 5-HT1A receptor agonist [67]. Abnormal mitochondrial functions were revealed in human Fragile X-associated tremor ataxia syndrome (the pre-mutation condition) [93] and in Fmr1 KO mice [94,95,96]. It would be very interesting to check if 5-HT1A receptor agonists might also rescue mitochondrial deficits in Fmr1 KO mice and in human Fragile X patients.

6. The Blockade of 5-HT5A Receptors Improved Behavior and Memory in a Rat Model of Fragile X Syndrome

Another possible target for Fragile X Syndrome therapy is the 5-HT5 receptor (Table 1). A recent study shows that Fmr1 KO rats displayed hyperactivity, abnormal sensory motor gating (as measured by the prepulse inhibition of startle protocol) and memory deficits (evaluated by the Novel Object Recognition test), and all these abnormal phenotypes were rescued by the oral administration of ASP5736, a selective 5-HT5A receptor antagonist [69]. As a possible action mechanism, the authors propose that the blockade of 5-HT5A receptors located on GABAergic interneurons in the ventral tegmental area might induce disinhibition and enhance GABA release onto dopaminergic neurons. Interestingly, the same authors had previously shown that the administration of ASP5736 also rescued cognitive deficits in aged rats [97] and in animal models of schizophrenia [98,99], pointing out 5-HT5 receptor antagonists as a new potential therapy tool in different conditions with cognitive impairment. The effects of drugs modulating serotonergic transmission in Fragile X patients and animal models are summarized in Table 1; Table 2 illustrates the main features of the serotonin receptors rescuing abnormal phenotypes in Fragile X animal models.

7. Conclusions

An overall enhancement of serotonergic transmission with SSRIs improves mood disorders and language deficits in Fragile X patients, and is already successfully used in therapy. Studies on Fragile X animal models further suggest that the selective modulation of the 5-HT1A, 5-HT2A, 5-HT2B, 5-HT5A and 5-HT7 receptors might be used to specifically correct other symptoms: these receptors, each having a different brain localization and activating different signaling mechanisms (Table 2), were shown to correct distinct malfunctions in Fragile X animal models. 5-HT1A agonists very effectively prevented seizures in Fmr1 KO mice, and therefore might be envisaged to treat epileptic Fragile X patients. 5-HT2A antagonists and 5-HT2B agonists rescued LTP and learning in Fmr1 KO mice, and thus might improve cognition. 5-HT5A antagonists reduced hyperactivity and improved cognition in Fmr1 KO rats, and thus might be used in Fragile X patients with concomitant attention deficit and hyperactivity disorder (ADHD). 5-HT7 agonists rescued synaptic plasticity, learning deficit and stereotyped behavior in Fmr1 KO mice, and therefore might be proposed to treat Fragile X patients with cognitive impairment and autistic features.
In conclusion, the treatment of Fragile X patients with SSRIs might be associated with drugs selectively acting on specific 5-HT receptor subtypes, depending on the patient’s symptoms. Future studies will better clarify the role of different 5-HT receptor subtypes in the disease in order to refine differential strategies for pharmacological intervention.
The development of new pharmacological strategies for Fragile X Syndrome is particularly important because we still lack an effective treatment, although several promising drug candidates are under investigation. Past clinical trials targeting metabotropic glutamate receptors have shown no significant improvements on Fragile X patients [100,101,102]. Other strategies aiming to correct malfunctions in brain GABAergic transmission have given disappointing results: the administration of ganaxolone, a neurosteroid positively modulating GABAA receptors, did not induce any significant improvement in anxiety, attention or hyperactivity in children with Fragile X Syndrome [103], and treatment with arbaclofen, a GABAB receptor agonist, did not improve social behavior [104].
On the other hand, other studies show promising results. A phase 2 clinical trial was conducted on 30 male Fragile X patients who were administered an inhibitor of phosphodiesterase 4 (PDE4) in order to enhance cAMP signaling (which is depressed in Fragile X Syndrome); results from this study show an improvement in cognition, language and daily functioning [105].
A combined treatment of lovastatin and minocycline was recently shown to reduce abnormal cortical excitability in Fragile X patients [106].
Another candidate drug for Fragile X therapy is metformin, based on the observation that the absence of FMRP leads to the increased brain production of Insulin-like Growth Factor 1 (IGF-1) [107]. A recent report from a clinical trial shows that metformin administration to young Fragile X patients (6–25 years old) prevented a decline in cognitive development and adaptive functioning, although this result needs to be confirmed in a large sample of patients [108].

8. Future Directions

Clinical studies might be designed to test the effects of drugs selectively targeting 5-HT receptor subtypes on Fragile X patients, alone or in association with SSRI treatment. Some of these drugs are already used in therapy, and thus their off-label use in Fragile X Syndrome might be envisaged.
Buspirone, a partial agonist of 5-HT1A receptors, is used as an antidepressant and anxiolytic [109]. The atypical antipsychotic aripiprazole, besides activating the D2 and D3 dopamine receptors, has a partial agonist activity at 5-HT1A receptors and an antagonist activity at 5-HT2A receptors [110] and is at present used to treat Fragile X patients with aggressive and self-injurious behavior [111]. Pimavanserin, a new generation 5-HT2A selective antagonist, has been clinically tested as an antipsychotic in Parkinson’s disease and schizophrenia; its pharmacokinetic properties, safety and tolerability have been characterized in humans [112]. New selective 5-HT7 receptor agonists with drug-like properties have been synthetized and tested in pre-clinical studies on Fmr1 KO mice [71,113]. Interestingly, a set of arylpiperazine derivatives with a mixed 5-HT1A/5-HT7 agonist and 5-HT2A antagonist activity, a good in vitro metabolic stability, drug-like properties and the ability to cross the blood–brain barrier have recently been proposed as a potential tool to treat autism spectrum disorders [114]; based on their mixed pharmacological properties, we suggest that these compounds might be tested in preclinical studies on animal models of Fragile X Syndrome.

Author Contributions

Conceptualization, writing—original draft preparation and funding acquisition, L.C. (Lucia Ciranna); investigation and writing—review and figure editing, L.C. (Lara Costa). All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the MUR under project P2022XPAW4; call PRIN 2022 PNRR.

Acknowledgments

We wish to thank Maija Castrén (University of Helsinki, Finland), Enza Lacivita (University of Bari, Italy) and Marcello Leopoldo (University of Bari, Italy) for the critical reading of the manuscript. Parts of images from the Motifolio drawing toolkit (www.motifolio.com) were utilized in figure preparation.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Sodhi, M.S.; Sanders-Bush, E. Serotonin and brain development. Int. Rev. Neurobiol. 2004, 59, 111–174. [Google Scholar] [PubMed]
  2. Wirth, A.; Holst, K.; Ponimaskin, E. How serotonin receptors regulate morphogenic signalling in neurons. Prog. Neurobiol. 2017, 151, 35–56. [Google Scholar] [CrossRef] [PubMed]
  3. Chugani, D.C. Role of altered brain serotonin mechanisms in autism. Mol. Psychiatry 2002, 7 (Suppl. 2), S16–S17. [Google Scholar] [CrossRef] [PubMed]
  4. Hannon, J.; Hoyer, D. Molecular biology of 5-HT receptors. Behav. Brain Res. 2008, 195, 198–213. [Google Scholar] [CrossRef]
  5. Yu, Y.; Cao, D.Q.; Xu, H.Y.; Sun, M.; Huang, Z.L.; Yung, W.H.; Lu, N.; Huang, Y. 5-HT3A receptors are required in long-term depression and AMPA receptor internalization. Neuroscience 2014, 278, 105–112. [Google Scholar] [CrossRef]
  6. Staubli, U.; Xu, F.B. Effects of 5-HT3 receptor antagonism on hippocampal theta rhythm, memory, and LTP induction in the freely moving rat. J. Neurosci. 1995, 15 Pt 2, 2445–2452. [Google Scholar] [CrossRef]
  7. Bockaert, J.; Sebben, M.; Dumuis, A. Pharmacological characterization of 5-hydroxytryptamine4(5-HT4) receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: Effect of substituted benzamide derivatives. Mol. Pharmacol. 1990, 37, 408–411. [Google Scholar] [CrossRef]
  8. Dumuis, A.; Sebben, M.; Bockaert, J. BRL 24924: A potent agonist at a non-classical 5-HT receptor positively coupled with adenylate cyclase in colliculi neurons. Eur. J. Pharmacol. 1989, 162, 381–384. [Google Scholar] [CrossRef]
  9. Restivo, L.; Roman, F.; Dumuis, A.; Bockaert, J.; Marchetti, E.; Ammassari-Teule, M. The promnesic effect of G-protein-coupled 5-HT4 receptors activation is mediated by a potentiation of learning-induced spine growth in the mouse hippocampus. Neuropsychopharmacology 2008, 33, 2427–2434. [Google Scholar] [CrossRef]
  10. Marchetti, E.; Chaillan, F.A.; Dumuis, A.; Bockaert, J.; Soumireu-Mourat, B.; Roman, F.S. Modulation of memory processes and cellular excitability in the dentate gyrus of freely moving rats by a 5-HT4 receptors partial agonist, and an antagonist. Neuropharmacology 2004, 47, 1021–1035. [Google Scholar] [CrossRef]
  11. Thomas, D.R. 5-ht5A receptors as a therapeutic target. Pharmacol. Ther. 2006, 111, 707–714. [Google Scholar] [CrossRef] [PubMed]
  12. Marazziti, D.; Baroni, S.; Borsini, F.; Picchetti, M.; Vatteroni, E.; Falaschi, V.; Catena-Dell’Osso, M. Serotonin receptors of type 6 (5-HT6): From neuroscience to clinical pharmacology. Curr. Med. Chem. 2013, 20, 371–377. [Google Scholar]
  13. Ruat, M.; Traiffort, E.; Leurs, R.; Tardivel-Lacombe, J.; Diaz, J.; Arrang, J.M.; Schwartz, J.C. Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation. Proc. Natl. Acad. Sci. USA 1993, 90, 8547–8551. [Google Scholar] [CrossRef] [PubMed]
  14. Monsma, F.J., Jr.; Shen, Y.; Ward, R.P.; Hamblin, M.W.; Sibley, D.R. Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol. Pharmacol. 1993, 43, 320–327. [Google Scholar] [CrossRef] [PubMed]
  15. Lovenberg, T.W.; Baron, B.M.; de Lecea, L.; Miller, J.D.; Prosser, R.A.; Rea, M.A.; Foye, P.E.; Racke, M.; Slone, A.L.; Siegel, B.W.; et al. A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms. Neuron 1993, 11, 449–458. [Google Scholar] [CrossRef]
  16. Hedlund, P.B.; Sutcliffe, J.G. Functional, molecular and pharmacological advances in 5-HT7 receptor research. Trends Pharmacol. Sci. 2004, 25, 481–486. [Google Scholar] [CrossRef]
  17. Martin-Cora, F.J.; Pazos, A. Autoradiographic distribution of 5-HT7 receptors in the human brain using [3H]mesulergine: Comparison to other mammalian species. Br. J. Pharmacol. 2004, 141, 92–104. [Google Scholar] [CrossRef]
  18. Varnas, K.; Thomas, D.R.; Tupala, E.; Tiihonen, J.; Hall, H. Distribution of 5-HT7 receptors in the human brain: A preliminary autoradiographic study using [3H]SB-269970. Neurosci. Lett. 2004, 367, 313–316. [Google Scholar] [CrossRef]
  19. Bard, J.A.; Zgombick, J.; Adham, N.; Vaysse, P.; Branchek, T.A.; Weinshank, R.L. Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase. J. Biol. Chem. 1993, 268, 23422–23426. [Google Scholar] [CrossRef]
  20. Norum, J.H.; Hart, K.; Levy, F.O. Ras-dependent ERK activation by the human G(s)-coupled serotonin receptors 5-HT4(b) and 5-HT7(a). J. Biol. Chem. 2003, 278, 3098–3104. [Google Scholar] [CrossRef]
  21. Lin, S.L.; Johnson-Farley, N.N.; Lubinsky, D.R.; Cowen, D.S. Coupling of neuronal 5-HT7 receptors to activation of extracellular-regulated kinase through a protein kinase A-independent pathway that can utilize Epac. J. Neurochem. 2003, 87, 1076–1085. [Google Scholar] [CrossRef] [PubMed]
  22. Errico, M.; Crozier, R.A.; Plummer, M.R.; Cowen, D.S. 5-HT(7) receptors activate the mitogen activated protein kinase extracellular signal related kinase in cultured rat hippocampal neurons. Neuroscience 2001, 102, 361–367. [Google Scholar] [CrossRef]
  23. Hoffman, M.S.; Mitchell, G.S. Spinal 5-HT7 receptor activation induces long-lasting phrenic motor facilitation. J. Physiol. 2011, 589 Pt 6, 1397–1407. [Google Scholar] [CrossRef]
  24. Johnson-Farley, N.N.; Kertesy, S.B.; Dubyak, G.R.; Cowen, D.S. Enhanced activation of Akt and extracellular-regulated kinase pathways by simultaneous occupancy of Gq-coupled 5-HT2A receptors and Gs-coupled 5-HT7A receptors in PC12 cells. J. Neurochem. 2005, 92, 72–82. [Google Scholar] [CrossRef] [PubMed]
  25. Kvachnina, E.; Liu, G.; Dityatev, A.; Renner, U.; Dumuis, A.; Richter, D.W.; Dityateva, G.; Schachner, M.; Voyno-Yasenetskaya, T.A.; Ponimaskin, E.G. 5-HT7 receptor is coupled to G alpha subunits of heterotrimeric G12-protein to regulate gene transcription and neuronal morphology. J. Neurosci. 2005, 25, 7821–7830. [Google Scholar] [CrossRef] [PubMed]
  26. Hall, A. G proteins and small GTPases: Distant relatives keep in touch. Science 1998, 280, 2074–2075. [Google Scholar] [CrossRef]
  27. Matthys, A.; Haegeman, G.; Van Craenenbroeck, K.; Vanhoenacker, P. Role of the 5-HT7 receptor in the central nervous system: From current status to future perspectives. Mol. Neurobiol. 2011, 43, 228–253. [Google Scholar] [CrossRef]
  28. Kobe, F.; Guseva, D.; Jensen, T.P.; Wirth, A.; Renner, U.; Hess, D.; Muller, M.; Medrihan, L.; Zhang, W.; Zhang, M.; et al. 5-HT7R/G12 signaling regulates neuronal morphology and function in an age-dependent manner. J. Neurosci. 2012, 32, 2915–2930. [Google Scholar] [CrossRef]
  29. Speranza, L.; Giuliano, T.; Volpicelli, F.; De Stefano, M.E.; Lombardi, L.; Chambery, A.; Lacivita, E.; Leopoldo, M.; Bellenchi, G.C.; di Porzio, U.; et al. Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics. Front. Behav. Neurosci. 2015, 9, 62. [Google Scholar] [CrossRef]
  30. Meneses, A.; Perez-Garcia, G.; Liy-Salmeron, G.; Ponce-Lopez, T.; Lacivita, E.; Leopoldo, M. 5-HT7 receptor activation: Procognitive and antiamnesic effects. Psychopharmacology 2015, 232, 595–603. [Google Scholar] [CrossRef]
  31. Eriksson, T.M.; Holst, S.; Stan, T.L.; Hager, T.; Sjogren, B.; Ogren, S.O.; Svenningsson, P.; Stiedl, O. 5-HT1A and 5-HT7 receptor crosstalk in the regulation of emotional memory: Implications for effects of selective serotonin reuptake inhibitors. Neuropharmacology 2012, 63, 1150–1160. [Google Scholar] [CrossRef] [PubMed]
  32. Ciranna, L.; Catania, M.V. 5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: Physiological role and possible implications in autism spectrum disorders. Front. Cell Neurosci. 2014, 8, 250. [Google Scholar] [CrossRef] [PubMed]
  33. Hagerman, P.J.; Hagerman, R. Fragile X syndrome. Curr. Biol. 2021, 31, R273–R275. [Google Scholar] [CrossRef] [PubMed]
  34. Wijetunge, L.S.; Chattarji, S.; Wyllie, D.J.; Kind, P.C. Fragile X syndrome: From targets to treatments. Neuropharmacology 2013, 68, 83–96. [Google Scholar] [CrossRef]
  35. Weiler, I.J.; Irwin, S.A.; Klintsova, A.Y.; Spencer, C.M.; Brazelton, A.D.; Miyashiro, K.; Comery, T.A.; Patel, B.; Eberwine, J.; Greenough, W.T. Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. Proc. Natl. Acad. Sci. USA 1997, 94, 5395–5400. [Google Scholar] [CrossRef]
  36. Pfeiffer, B.E.; Huber, K.M. The State of Synapses in Fragile X Syndrome. Neuroscientist 2009. [CrossRef]
  37. Bardoni, B.; Davidovic, L.; Bensaid, M.; Khandjian, E.W. The fragile X syndrome: Exploring its molecular basis and seeking a treatment. Expert. Rev. Mol. Med. 2006, 8, 1–16. [Google Scholar] [CrossRef]
  38. Irwin, S.A.; Patel, B.; Idupulapati, M.; Harris, J.B.; Crisostomo, R.A.; Larsen, B.P.; Kooy, F.; Willems, P.J.; Cras, P.; Kozlowski, P.B.; et al. Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: A quantitative examination. Am. J. Med. Genet. 2001, 98, 161–167. [Google Scholar] [CrossRef]
  39. Comery, T.A.; Harris, J.B.; Willems, P.J.; Oostra, B.A.; Irwin, S.A.; Weiler, I.J.; Greenough, W.T. Abnormal dendritic spines in fragile X knockout mice: Maturation and pruning deficits. Proc. Natl. Acad. Sci. USA 1997, 94, 5401–5404. [Google Scholar] [CrossRef]
  40. Huber, K.M.; Gallagher, S.M.; Warren, S.T.; Bear, M.F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl. Acad. Sci. USA 2002, 99, 7746–7750. [Google Scholar] [CrossRef]
  41. Bear, M.F.; Huber, K.M.; Warren, S.T. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004, 27, 370–377. [Google Scholar] [CrossRef] [PubMed]
  42. Giuffrida, R.; Musumeci, S.; D’Antoni, S.; Bonaccorso, C.M.; Giuffrida-Stella, A.M.; Oostra, B.A.; Catania, M.V. A reduced number of metabotropic glutamate subtype 5 receptors are associated with constitutive homer proteins in a mouse model of fragile X syndrome. J. Neurosci. 2005, 25, 8908–8916. [Google Scholar] [CrossRef] [PubMed]
  43. Aloisi, E.; Le Corf, K.; Dupuis, J.; Zhang, P.; Ginger, M.; Labrousse, V.; Spatuzza, M.; Georg Haberl, M.; Costa, L.; Shigemoto, R.; et al. Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice. Nat. Commun. 2017, 8, 1103. [Google Scholar] [CrossRef] [PubMed]
  44. Yun, S.H.; Trommer, B.L. Fragile X mice: Reduced long-term potentiation and N-Methyl-D-Aspartate receptor-mediated neurotransmission in dentate gyrus. J. Neurosci. Res. 2011, 89, 176–182. [Google Scholar] [CrossRef]
  45. Gocel, J.; Larson, J. Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse. Neuroscience 2012, 221, 170–181. [Google Scholar] [CrossRef]
  46. Bostrom, C.A.; Majaess, N.M.; Morch, K.; White, E.; Eadie, B.D.; Christie, B.R. Rescue of NMDAR-Dependent Synaptic Plasticity in Fmr1 Knock-Out Mice. Cereb. Cortex 2015, 25, 271–279. [Google Scholar] [CrossRef]
  47. Uzunova, G.; Hollander, E.; Shepherd, J. The role of ionotropic glutamate receptors in childhood neurodevelopmental disorders: Autism spectrum disorders and fragile x syndrome. Curr. Neuropharmacol. 2014, 12, 71–98. [Google Scholar] [CrossRef]
  48. D’Hulst, C.; De Geest, N.; Reeve, S.P.; Van Dam, D.; De Deyn, P.P.; Hassan, B.A.; Kooy, R.F. Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res. 2006, 1121, 238–245. [Google Scholar] [CrossRef]
  49. Curia, G.; Papouin, T.; Seguela, P.; Avoli, M. Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome. Cereb. Cortex 2009, 19, 1515–1520. [Google Scholar] [CrossRef]
  50. Braat, S.; Kooy, R.F. Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials. Neuropharmacology 2015, 88, 48–54. [Google Scholar] [CrossRef]
  51. Martin, B.S.; Corbin, J.G.; Huntsman, M.M. Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala. J. Neurophysiol. 2014, 112, 890–902. [Google Scholar] [CrossRef] [PubMed]
  52. Garber, K.B.; Visootsak, J.; Warren, S.T. Fragile X syndrome. Eur. J. Hum. Genet. 2008, 16, 666–672. [Google Scholar] [CrossRef] [PubMed]
  53. Bernardet, M.; Crusio, W.E. Fmr1 KO mice as a possible model of autistic features. Sci. World J. 2006, 6, 1164–1176. [Google Scholar] [CrossRef]
  54. Hanson, A.C.; Hagerman, R.J. Serotonin dysregulation in Fragile X Syndrome: Implications for treatment. Intractable Rare Dis. Res. 2014, 3, 110–117. [Google Scholar] [CrossRef]
  55. Hessl, D.; Tassone, F.; Cordeiro, L.; Koldewyn, K.; McCormick, C.; Green, C.; Wegelin, J.; Yuhas, J.; Hagerman, R.J. Brief report: Aggression and stereotypic behavior in males with fragile X syndrome--moderating secondary genes in a “single gene” disorder. J. Autism Dev. Disord. 2008, 38, 184–189. [Google Scholar] [CrossRef] [PubMed]
  56. McCarthy, D.M.; Vied, C.; Trupiano, M.X.; Canekeratne, A.J.; Wang, Y.; Schatschneider, C.; Bhide, P.G. Behavioral, neurotransmitter and transcriptomic analyses in male and female Fmr1 KO mice. Front. Behav. Neurosci. 2024, 18, 1458502. [Google Scholar] [CrossRef]
  57. Uutela, M.; Lindholm, J.; Rantamaki, T.; Umemori, J.; Hunter, K.; Voikar, V.; Castren, M.L. Distinctive behavioral and cellular responses to fluoxetine in the mouse model for Fragile X syndrome. Front. Cell Neurosci. 2014, 8, 150. [Google Scholar] [CrossRef]
  58. Quinlan, M.A.; Robson, M.J.; Ye, R.; Rose, K.L.; Schey, K.L.; Blakely, R.D. Ex vivo Quantitative Proteomic Analysis of Serotonin Transporter Interactome: Network Impact of the SERT Ala56 Coding Variant. Front. Mol. Neurosci. 2020, 13, 89. [Google Scholar] [CrossRef]
  59. Winarni, T.I.; Schneider, A.; Borodyanskara, M.; Hagerman, R.J. Early intervention combined with targeted treatment promotes cognitive and behavioral improvements in young children with fragile x syndrome. Case Rep. Genet. 2012, 2012, 280813. [Google Scholar] [CrossRef]
  60. Greiss Hess, L.; Fitzpatrick, S.E.; Nguyen, D.V.; Chen, Y.; Gaul, K.N.; Schneider, A.; Lemons Chitwood, K.; Eldeeb, M.A.; Polussa, J.; Hessl, D.; et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Low-Dose Sertraline in Young Children With Fragile X Syndrome. J. Dev. Behav. Pediatr. 2016, 37, 619–628. [Google Scholar] [CrossRef]
  61. Rajaratnam, A.; Potter, L.A.; Biag, H.M.B.; Schneider, A.; Petrasic, I.C.; Hagerman, R.J. Review of Autism Profiles and Response to Sertraline in Fragile X Syndrome-Associated Autism vs. Non-syndromic Autism; Next Steps for Targeted Treatment. Front. Neurol. 2020, 11, 581429. [Google Scholar] [CrossRef] [PubMed]
  62. AlOlaby, R.R.; Sweha, S.R.; Silva, M.; Durbin-Johnson, B.; Yrigollen, C.M.; Pretto, D.; Hagerman, R.J.; Tassone, F. Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome. Brain Dev. 2017, 39, 483–492. [Google Scholar] [CrossRef] [PubMed]
  63. Armstrong, J.L.; Casey, A.B.; Saraf, T.S.; Mukherjee, M.; Booth, R.G.; Canal, C.E. (S)-5-(2′-Fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder. ACS Pharmacol. Transl. Sci. 2020, 3, 509–523. [Google Scholar] [PubMed]
  64. Saraf, T.S.; McGlynn, R.P.; Bhatavdekar, O.M.; Booth, R.G.; Canal, C.E. FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT(1A), 5-HT(1B), and 5-HT(1D) Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice. ACS Chem. Neurosci. 2022, 13, 3629–3640. [Google Scholar] [CrossRef]
  65. Tao, X.; Newman-Tancredi, A.; Varney, M.A.; Razak, K.A. Acute and Repeated Administration of NLX-101, a Selective Serotonin-1A Receptor Biased Agonist, Reduces Audiogenic Seizures in Developing Fmr1 Knockout Mice. Neuroscience 2023, 509, 113–124. [Google Scholar] [CrossRef]
  66. Saraf, T.S.; Chen, Y.; Tyagi, R.; Canal, C.E. Altered brain serotonin 5-HT(1A) receptor expression and function in juvenile Fmr1 knockout mice. Neuropharmacology 2024, 245, 109774. [Google Scholar] [CrossRef]
  67. Vannelli, A.; Mariano, V.; Bagni, C.; Kanellopoulos, A.K. Activation of the 5-HT1A Receptor by Eltoprazine Restores Mitochondrial and Motor Deficits in a Drosophila Model of Fragile X Syndrome. Int. J. Mol. Sci. 2024, 25, 8787. [Google Scholar] [CrossRef]
  68. Lim, C.S.; Hoang, E.T.; Viar, K.E.; Stornetta, R.L.; Scott, M.M.; Zhu, J.J. Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model. Genes. Dev. 2014, 28, 273–289. [Google Scholar] [CrossRef]
  69. Yamazaki, M.; Arai, T.; Yarimizu, J.; Matsumoto, M. 5-HT5A Receptor Antagonist ASP5736 Ameliorates Several Abnormal Behaviors in an Fmr1-Targeted Transgenic Male Rat Model of Fragile X Syndrome. Int. J. Neuropsychopharmacol. 2022, 25, 786–793. [Google Scholar] [CrossRef]
  70. Costa, L.; Spatuzza, M.; D’Antoni, S.; Bonaccorso, C.M.; Trovato, C.; Musumeci, S.A.; Leopoldo, M.; Lacivita, E.; Catania, M.V.; Ciranna, L. Activation of 5-HT7 serotonin receptors reverses metabotropic glutamate receptor-mediated synaptic plasticity in wild-type and Fmr1 knockout mice, a model of Fragile X syndrome. Biol. Psychiatry 2012, 72, 924–933. [Google Scholar] [CrossRef]
  71. Costa, L.; Sardone, L.M.; Lacivita, E.; Leopoldo, M.; Ciranna, L. Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome. Front. Behav. Neurosci. 2015, 9, 65. [Google Scholar] [CrossRef]
  72. Costa, L.; Sardone, L.M.; Bonaccorso, C.M.; D’Antoni, S.; Spatuzza, M.; Gulisano, W.; Tropea, M.R.; Puzzo, D.; Leopoldo, M.; Lacivita, E.; et al. Activation of Serotonin 5-HT7 Receptors Modulates Hippocampal Synaptic Plasticity by Stimulation of Adenylate Cyclases and Rescues Learning and Behavior in a Mouse Model of Fragile X Syndrome. Front. Mol. Neurosci. 2018, 11, 353. [Google Scholar] [CrossRef] [PubMed]
  73. Sharghi, S.; Flunkert, S.; Daurer, M.; Rabl, R.; Chagnaud, B.P.; Leopoldo, M.; Lacivita, E.; Hutter-Paier, B.; Prokesch, M. Evaluating the effect of R-Baclofen and LP-211 on autistic behavior of the BTBR and Fmr1-KO mouse models. Front. Neurosci. 2023, 17, 1087788. [Google Scholar] [CrossRef] [PubMed]
  74. Hagan, J.J.; Price, G.W.; Jeffrey, P.; Deeks, N.J.; Stean, T.; Piper, D.; Smith, M.I.; Upton, N.; Medhurst, A.D.; Middlemiss, D.N.; et al. Characterization of SB-269970-A, a selective 5-HT(7) receptor antagonist. Br. J. Pharmacol. 2000, 130, 539–548. [Google Scholar] [CrossRef] [PubMed]
  75. Costa, L.; Trovato, C.; Musumeci, S.A.; Catania, M.V.; Ciranna, L. 5-HT(1A) and 5-HT(7) receptors differently modulate AMPA receptor-mediated hippocampal synaptic transmission. Hippocampus 2012, 22, 790–801. [Google Scholar] [CrossRef]
  76. Berry-Kravis, E.; Sklena, P. Demonstration of abnormal cyclic AMP production in platelets from patients with fragile X syndrome. Am. J. Med. Genet. 1993, 45, 81–87. [Google Scholar] [CrossRef]
  77. Berry-Kravis, E.; Huttenlocher, P.R. Cyclic AMP metabolism in fragile X syndrome. Ann. Neurol. 1992, 31, 22–26. [Google Scholar] [CrossRef]
  78. Kelley, D.J.; Davidson, R.J.; Elliott, J.L.; Lahvis, G.P.; Yin, J.C.; Bhattacharyya, A. The cyclic AMP cascade is altered in the fragile X nervous system. PLoS ONE 2007, 2, e931. [Google Scholar] [CrossRef]
  79. Maurin, T.; Lebrigand, K.; Castagnola, S.; Paquet, A.; Jarjat, M.; Popa, A.; Grossi, M.; Rage, F.; Bardoni, B. HITS-CLIP in various brain areas reveals new targets and new modalities of RNA binding by fragile X mental retardation protein. Nucleic Acids Res. 2018, 46, 6344–6355. [Google Scholar] [CrossRef]
  80. Maurin, T.; Melancia, F.; Jarjat, M.; Castro, L.; Costa, L.; Delhaye, S.; Khayachi, A.; Castagnola, S.; Mota, E.; Di Giorgio, A.; et al. Involvement of Phosphodiesterase 2A Activity in the Pathophysiology of Fragile X Syndrome. Cereb. Cortex 2019, 29, 3241–3252. [Google Scholar] [CrossRef]
  81. Costa, L.; Tempio, A.; Lacivita, E.; Leopoldo, M.; Ciranna, L. Serotonin 5-HT7 receptors require cyclin-dependent kinase 5 to rescue hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome. Eur. J. Neurosci. 2021, 54, 4124–4132. [Google Scholar] [CrossRef] [PubMed]
  82. Pao, P.C.; Tsai, L.H. Three decades of Cdk5. J. Biomed. Sci. 2021, 28, 79. [Google Scholar] [CrossRef] [PubMed]
  83. Ao, C.; Li, C.; Chen, J.; Tan, J.; Zeng, L. The role of Cdk5 in neurological disorders. Front. Cell Neurosci. 2022, 16, 951202. [Google Scholar] [CrossRef] [PubMed]
  84. Zhang, M.; Li, X.; Xiao, D.; Lu, T.; Qin, B.; Zheng, Z.; Zhang, Y.; Liu, Y.; Yan, T.; Han, X. Identification of differentially expressed microRNAs and their target genes in the hippocampal tissues of Fmr1 knockout mice. Am. J. Transl. Res. 2020, 12, 813–824. [Google Scholar]
  85. Lin, L.; Hu, X.; Hong, W.; Pan, T.; Wang, Z.; Wang, E.; Wu, G. A novel animal model of spontaneous epilepsy: Cdk5 knockout in pericyte-specific mice. Front. Cell Neurosci. 2024, 18, 1474231. [Google Scholar] [CrossRef]
  86. Fernandez, G.; Krapacher, F.; Ferreras, S.; Quassollo, G.; Mari, M.M.; Pisano, M.V.; Montemerlo, A.; Rubianes, M.D.; Bregonzio, C.; Arias, C.; et al. Lack of Cdk5 activity is involved on Dopamine Transporter expression and function: Evidences from an animal model of Attention-Deficit Hyperactivity Disorder. Exp. Neurol. 2021, 346, 113866. [Google Scholar] [CrossRef]
  87. Hedlund, P.B.; Leopoldo, M.; Caccia, S.; Sarkisyan, G.; Fracasso, C.; Martelli, G.; Lacivita, E.; Berardi, F.; Perrone, R. LP-211 is a brain penetrant selective agonist for the serotonin 5-HT(7) receptor. Neurosci. Lett. 2010, 481, 12–16. [Google Scholar] [CrossRef]
  88. Edagawa, Y.; Saito, H.; Abe, K. The serotonin 5-HT2 receptor-phospholipase C system inhibits the induction of long-term potentiation in the rat visual cortex. Eur. J. Neurosci. 2000, 12, 1391–1396. [Google Scholar] [CrossRef]
  89. Xu, Z.H.; Yang, Q.; Ma, L.; Liu, S.B.; Chen, G.S.; Wu, Y.M.; Li, X.Q.; Liu, G.; Zhao, M.G. Deficits in LTP induction by 5-HT2A receptor antagonist in a mouse model for fragile X syndrome. PLoS ONE 2012, 7, e48741. [Google Scholar] [CrossRef]
  90. Edagawa, Y.; Saito, H.; Abe, K. Stimulation of the 5-HT1A receptor selectively suppresses NMDA receptor-mediated synaptic excitation in the rat visual cortex. Brain Res. 1999, 827, 225–228. [Google Scholar] [CrossRef]
  91. Edagawa, Y.; Saito, H.; Abe, K. Serotonin inhibits the induction of long-term potentiation in rat primary visual cortex. Prog. Neuropsychopharmacol. Biol. Psychiatry 1998, 22, 983–997. [Google Scholar] [CrossRef] [PubMed]
  92. Canal, C.E.; Felsing, D.E.; Liu, Y.; Zhu, W.; Wood, J.T.; Perry, C.K.; Vemula, R.; Booth, R.G. An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist that Corrects Motor Stereotypy in Mouse Models. ACS Chem. Neurosci. 2015, 6, 1259–1270. [Google Scholar] [CrossRef]
  93. Song, G.; Napoli, E.; Wong, S.; Hagerman, R.; Liu, S.; Tassone, F.; Giulivi, C. Altered redox mitochondrial biology in the neurodegenerative disorder fragile X-tremor/ataxia syndrome: Use of antioxidants in precision medicine. Mol. Med. 2016, 22, 548–559. [Google Scholar] [CrossRef] [PubMed]
  94. Shen, M.; Wang, F.; Li, M.; Sah, N.; Stockton, M.E.; Tidei, J.J.; Gao, Y.; Korabelnikov, T.; Kannan, S.; Vevea, J.D.; et al. Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice. Nat. Neurosci. 2019, 22, 386–400. [Google Scholar] [CrossRef] [PubMed]
  95. D’Antoni, S.; de Bari, L.; Valenti, D.; Borro, M.; Bonaccorso, C.M.; Simmaco, M.; Vacca, R.A.; Catania, M.V. Aberrant mitochondrial bioenergetics in the cerebral cortex of the Fmr1 knockout mouse model of fragile X syndrome. Biol. Chem. 2020, 401, 497–503. [Google Scholar] [CrossRef]
  96. Griffiths, K.K.; Wang, A.; Wang, L.; Tracey, M.; Kleiner, G.; Quinzii, C.M.; Sun, L.; Yang, G.; Perez-Zoghbi, J.F.; Licznerski, P.; et al. Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome. FASEB J. 2020, 34, 7404–7426. [Google Scholar] [CrossRef]
  97. Yamazaki, M.; Okabe, M.; Yamamoto, N.; Yarimizu, J.; Harada, K. Novel 5-HT5A receptor antagonists ameliorate scopolamine-induced working memory deficit in mice and reference memory impairment in aged rats. J. Pharmacol. Sci. 2015, 127, 362–369. [Google Scholar] [CrossRef]
  98. Yamazaki, M.; Yamamoto, N.; Yarimizu, J.; Okabe, M.; Moriyama, A.; Furutani, M.; Marcus, M.M.; Svensson, T.H.; Harada, K. Functional mechanism of ASP5736, a selective serotonin 5-HT(5A) receptor antagonist with potential utility for the treatment of cognitive dysfunction in schizophrenia. Eur. Neuropsychopharmacol. 2018, 28, 620–629. [Google Scholar] [CrossRef]
  99. Yamazaki, M.; Harada, K.; Yamamoto, N.; Yarimizu, J.; Okabe, M.; Shimada, T.; Ni, K.; Matsuoka, N. ASP5736, a novel 5-HT5A receptor antagonist, ameliorates positive symptoms and cognitive impairment in animal models of schizophrenia. Eur. Neuropsychopharmacol. 2014, 24, 1698–1708. [Google Scholar] [CrossRef]
  100. Youssef, E.A.; Berry-Kravis, E.; Czech, C.; Hagerman, R.J.; Hessl, D.; Wong, C.Y.; Rabbia, M.; Deptula, D.; John, A.; Kinch, R.; et al. Effect of the mGluR5-NAM Basimglurant on Behavior in Adolescents and Adults with Fragile X Syndrome in a Randomized, Double-Blind, Placebo-Controlled Trial: FragXis Phase 2 Results. Neuropsychopharmacology 2018, 43, 503–512. [Google Scholar] [CrossRef]
  101. Hagerman, R.; Jacquemont, S.; Berry-Kravis, E.; Des Portes, V.; Stanfield, A.; Koumaras, B.; Rosenkranz, G.; Murgia, A.; Wolf, C.; Apostol, G.; et al. Mavoglurant in Fragile X Syndrome: Results of two open-label, extension trials in adults and adolescents. Sci. Rep. 2018, 8, 16970. [Google Scholar] [CrossRef] [PubMed]
  102. Berry-Kravis, E.; Des Portes, V.; Hagerman, R.; Jacquemont, S.; Charles, P.; Visootsak, J.; Brinkman, M.; Rerat, K.; Koumaras, B.; Zhu, L.; et al. Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials. Sci. Transl. Med. 2016, 8, 321ra325. [Google Scholar] [CrossRef] [PubMed]
  103. Ligsay, A.; Van Dijck, A.; Nguyen, D.V.; Lozano, R.; Chen, Y.; Bickel, E.S.; Hessl, D.; Schneider, A.; Angkustsiri, K.; Tassone, F.; et al. A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome. J. Neurodev. Disord. 2017, 9, 26. [Google Scholar] [CrossRef]
  104. Berry-Kravis, E.; Hagerman, R.; Visootsak, J.; Budimirovic, D.; Kaufmann, W.E.; Cherubini, M.; Zarevics, P.; Walton-Bowen, K.; Wang, P.; Bear, M.F.; et al. Arbaclofen in fragile X syndrome: Results of phase 3 trials. J. Neurodev. Disord. 2017, 9, 3. [Google Scholar] [CrossRef] [PubMed]
  105. Berry-Kravis, E.M.; Harnett, M.D.; Reines, S.A.; Reese, M.A.; Ethridge, L.E.; Outterson, A.H.; Michalak, C.; Furman, J.; Gurney, M.E. Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: A randomized, placebo-controlled, phase 2 clinical trial. Nat. Med. 2021, 27, 862–870. [Google Scholar] [CrossRef]
  106. Morin-Parent, F.; Champigny, C.; Cote, S.; Mohamad, T.; Hasani, S.A.; Caku, A.; Corbin, F.; Lepage, J.F. Neurophysiological effects of a combined treatment of lovastatin and minocycline in patients with fragile X syndrome: Ancillary results of the LOVAMIX randomized clinical trial. Autism Res. 2024, 17, 1944–1956. [Google Scholar] [CrossRef]
  107. Proteau-Lemieux, M.; Lacroix, A.; Galarneau, L.; Corbin, F.; Lepage, J.F.; Caku, A. The safety and efficacy of metformin in fragile X syndrome: An open-label study. Prog. Neuropsychopharmacol. Biol. Psychiatry 2021, 110, 110307. [Google Scholar] [CrossRef]
  108. Seng, P.; Montanaro, F.A.M.; Biag, H.M.B.; Salcedo-Arellano, M.J.; Kim, K.; Ponzini, M.D.; Tassone, F.; Schneider, A.; Abbeduto, L.; Thurman, A.J.; et al. Longitudinal follow-up of metformin treatment in Fragile X Syndrome. Front. Psychol. 2024, 15, 1305597. [Google Scholar] [CrossRef]
  109. Loane, C.; Politis, M. Buspirone: What is it all about? Brain Res. 2012, 1461, 111–118. [Google Scholar] [CrossRef]
  110. Casey, A.B.; Canal, C.E. Classics in Chemical Neuroscience: Aripiprazole. ACS Chem. Neurosci. 2017, 8, 1135–1146. [Google Scholar] [CrossRef]
  111. Eckert, E.M.; Dominick, K.C.; Pedapati, E.V.; Wink, L.K.; Shaffer, R.C.; Andrews, H.; Choo, T.H.; Chen, C.; Kaufmann, W.E.; Tartaglia, N.; et al. Pharmacologic Interventions for Irritability, Aggression, Agitation and Self-Injurious Behavior in Fragile X Syndrome: An Initial Cross-Sectional Analysis. J. Autism Dev. Disord. 2019, 49, 4595–4602. [Google Scholar] [CrossRef] [PubMed]
  112. Pahwa, M.; Sleem, A.; Elsayed, O.H.; Good, M.E.; El-Mallakh, R.S. New Antipsychotic Medications in the Last Decade. Curr. Psychiatry Rep. 2021, 23, 87. [Google Scholar] [CrossRef] [PubMed]
  113. Lacivita, E.; Niso, M.; Stama, M.L.; Arzuaga, A.; Altamura, C.; Costa, L.; Desaphy, J.F.; Ragozzino, M.E.; Ciranna, L.; Leopoldo, M. Privileged scaffold-based design to identify a novel drug-like 5-HT7 receptor-preferring agonist to target Fragile X syndrome. Eur. J. Med. Chem. 2020, 199, 112395. [Google Scholar] [CrossRef] [PubMed]
  114. Lacivita, E.; Niso, M.; Mastromarino, M.; Garcia Silva, A.; Resch, C.; Zeug, A.; Loza, M.I.; Castro, M.; Ponimaskin, E.; Leopoldo, M. Knowledge-Based Design of Long-Chain Arylpiperazine Derivatives Targeting Multiple Serotonin Receptors as Potential Candidates for Treatment of Autism Spectrum Disorder. ACS Chem. Neurosci. 2021, 12, 1313–1327. [Google Scholar] [CrossRef]
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Figure 1. The activation of 5-HT7 receptors corrected exaggerated mGluR-LTD, improved learning and reduced stereotyped behavior of Fmr1 KO mice. (A) In mouse hippocampal synapses between the CA3 and CA1 pyramidal neurons, the activation of group I metabotropic glutamate receptors induces long-term depression (mGluR-LTD), mediated by local protein synthesis, the activation of phosphatases and the endocytosis of AMPA glutamate receptors. In Fmr1 KO slices, the amount of mGluR-LTD was abnormally enhanced with respect to wild-type mice and was reduced by the application of LP-211, a selective 5-HT7 receptor agonist: the activation of 5-HT7 receptors prevented the mGluR-induced endocytosis of AMPA receptors and rescued mGluR-LTD to normal levels [70]. The effect of LP-211 was mediated by the activation of adenylate cyclase (AC), cAMP formation and the stimulation of protein kinase A (PKA) [72]. The 5-HT7 receptor-mediated rescue of mGluR-LTD also involved cyclin-dependent kinase 5, Cdk5 [81]; the intracellular pathway leading to Cdk5 activation is still to be clarified (dotted line). (B) The in vivo intraperitoneal injection of LP-211 into Fmr1 KO mice improved memory in Novel Object Recognition (NOR) test and reduced repetitive behavior, as measured by the marble burying test [81]. Parts of images from the Motifolio drawing toolkit (www.motifolio.com) were utilized in this figure.
Figure 1. The activation of 5-HT7 receptors corrected exaggerated mGluR-LTD, improved learning and reduced stereotyped behavior of Fmr1 KO mice. (A) In mouse hippocampal synapses between the CA3 and CA1 pyramidal neurons, the activation of group I metabotropic glutamate receptors induces long-term depression (mGluR-LTD), mediated by local protein synthesis, the activation of phosphatases and the endocytosis of AMPA glutamate receptors. In Fmr1 KO slices, the amount of mGluR-LTD was abnormally enhanced with respect to wild-type mice and was reduced by the application of LP-211, a selective 5-HT7 receptor agonist: the activation of 5-HT7 receptors prevented the mGluR-induced endocytosis of AMPA receptors and rescued mGluR-LTD to normal levels [70]. The effect of LP-211 was mediated by the activation of adenylate cyclase (AC), cAMP formation and the stimulation of protein kinase A (PKA) [72]. The 5-HT7 receptor-mediated rescue of mGluR-LTD also involved cyclin-dependent kinase 5, Cdk5 [81]; the intracellular pathway leading to Cdk5 activation is still to be clarified (dotted line). (B) The in vivo intraperitoneal injection of LP-211 into Fmr1 KO mice improved memory in Novel Object Recognition (NOR) test and reduced repetitive behavior, as measured by the marble burying test [81]. Parts of images from the Motifolio drawing toolkit (www.motifolio.com) were utilized in this figure.
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Table 2. Main features of 5-HT1A, 5-HT2A, 5-HT2B, 5-HT5A and 5-HT7 receptors for serotonin.
Table 2. Main features of 5-HT1A, 5-HT2A, 5-HT2B, 5-HT5A and 5-HT7 receptors for serotonin.
ReceptorBrain Localization
(Rodent; Human)		Transduction MechanismAgonistsAntagonistsReferences
5-HT1ALimbic areas; hippocampus; raphe nucleiInhibition of adenylate cyclase8-OH DPATWAY100635[4]
5-HT2ACerebral cortex; olfactory bulb; brainstem nucleiStimulation of phospholipase CDOIKetanserin
MDL100907		[4]
5-HT2BCerebellum; lateral septum; hypothalamus; amygdalaStimulation of phospholipase CBW723C86SB200646
SB204741		[4]
5-HT5AHippocampus; frontal cortex; raphe nucleiInhibition of adenylate cyclase 5-CT
8-OH DPAT		ASP5736[11]
[69]
5-HT7Thalamus; hypothalamus; hippocampusStimulation of adenylate cyclase 5-CT
8-OH DPAT
LP-211		SB269970
SB656104		[16];
[87]
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Ciranna, L.; Costa, L. Therapeutic Effects of Pharmacological Modulation of Serotonin Brain System in Human Patients and Animal Models of Fragile X Syndrome. Int. J. Mol. Sci. 2025, 26, 2495. https://doi.org/10.3390/ijms26062495

AMA Style

Ciranna L, Costa L. Therapeutic Effects of Pharmacological Modulation of Serotonin Brain System in Human Patients and Animal Models of Fragile X Syndrome. International Journal of Molecular Sciences. 2025; 26(6):2495. https://doi.org/10.3390/ijms26062495

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Ciranna, Lucia, and Lara Costa. 2025. "Therapeutic Effects of Pharmacological Modulation of Serotonin Brain System in Human Patients and Animal Models of Fragile X Syndrome" International Journal of Molecular Sciences 26, no. 6: 2495. https://doi.org/10.3390/ijms26062495

APA Style

Ciranna, L., & Costa, L. (2025). Therapeutic Effects of Pharmacological Modulation of Serotonin Brain System in Human Patients and Animal Models of Fragile X Syndrome. International Journal of Molecular Sciences, 26(6), 2495. https://doi.org/10.3390/ijms26062495

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