Search Results (283)

Background/Objectives: The neurotransmitter glycine is involved in several physiological and pathological conditions in the Central Nervous System. Different biological structures, including glycine receptors and transporters, are under study as targets for potential drugs acting against serious neurological and psychiatric disorders. The regulation of glycine release from nerve terminals is only partially understood. We report here preliminary evidence of the modulation of glycine release through presynaptic metabotropic glutamate receptors 1 (mGlu1) from glycinergic nerve terminals in mouse hippocampi. Methods: Purified mouse hippocampal synaptosomes labeled with [³H]glycine were used to study glycine release under superfusion conditions. Results: The group I metabotropic glutamate receptor agonist 3,5-DHPG potentiated depolarization-evoked [³H]glycine release from hippocampal synaptosomes, an effect strongly counteracted by the selective mGlu1 antagonist LY 367385. 3,5-DHPG failed to increase [³H]glycine release in Grm1^crv4/crv4 mice, a mouse model lacking mGlu1. Although further research is needed to clarify these mechanisms, data suggest that glycine-releasing hippocampal nerve terminals are endowed with presynaptic mGlu1 receptors whose activation potentiates glycine release. Conclusions: Considering that in the hippocampus, glycine is relevant as a co-agonist of glutamate at NMDA receptors and that mGlu1 receptor ligands are under study as potential drugs, we propose that the possible effects of these agents on the release of glycine should be considered when studying these compounds. Full article

The role of LAP proteins expressed in skeletal muscles (ERBIN, LANO, and SCRIBBLE) and at neuromuscular junctions (NMJs) remains largely unknown. Our previous data demonstrate that LAP proteins are differentially expressed in muscle cells, nerve endings, and terminal Schwann cells, though they are all expressed in myofibers and accumulate at NMJs. ERBIN and SCRIBBLE align with acetylcholine receptor clusters (CHRNs) at the NMJ. In vivo ablation of Erbin is associated with smaller CHRN and upregulation of Lano and Scribble. However, SCRIBBLE was also shown to influence the fate decision of muscle stem cells. Here, we investigated how the absence of SCRIBBLE in skeletal muscle cells might impair skeletal muscle fibers or NMJs. Although conditional Scribble knockout mice did not exhibit changes in weight or viability, force per weight decreased slightly. This was supported by compromised neuromuscular transmission and increased NMJ fragmentation. Moreover, Scribble knockout muscles transcribe less myosin heavy chain genes. Here, we also showed that RAB5, an effector of endocytic recycling, interacts with all LAP proteins, but in Scribble knockout muscles, reduced interaction was detected with ERBIN and LANO. These data suggest that a delicate signaling network employing LAP proteins is necessary for skeletal muscle fibers and NMJs. Full article

Background: Rabies virus (RABV) causes approximately 59,000 human deaths annually. Current pre- and post-exposure vaccination relies on inactivated vaccines (INVs) with limited yield and immunogenicity. We engineered a dual-cationic LNP-based nucleocapsid-like nanostructure (NLS) that co-encapsulates RABV G-mRNA and recombinant RABV-N to engage MHC-I/II pathways and enhance protection. Methods: A pVAX-RABV-G plasmid containing 5′/3′UTRs, Kozak, and poly(A) was transcribed in vitro. RABV-N with an N-terminal 6× His tag was expressed in E. coli BL21(DE3) and purified by Ni-Sepharose affinity chromatography. Dual-cationic LNPs (DHA, DOTAP Cl, mPEG-DTA2K, DOPC) were formulated by microfluidics at a 4:1 (G-mRNA:RABV-N) mass ratio. Vaccine quality was assessed by encapsulation efficiency, DLS, PDI, zeta potential, and TEM. Mice received empty LNPs, INV, G-mRNA, or NLS under varied schedules and doses. ELISA measured RABV-G/N-IgG; RFFIT determined neutralizing antibody (nAb) titers; ELISPOT quantified CTL response; qPCR assessed T-cell activation genes. On day 35 after the first immunization of vaccines, mice were challenged intramuscularly with 25 LD₅₀ of CVS-24. Results: G-mRNA purity was >95% and drove strong RABV-G expression in 293T cells. Purified RABV-N was approximately 52 kDa, >90% pure, and reactive to anti-His and anti-N antibodies. NLS achieved >95% encapsulation, a diameter of 136.9 nm, PDI 0.09, and a +18.7 mV zeta potential. A single dose yielded approximately 10 IU mL⁻¹ nAb by day 7; two doses peaked at approximately 1000 IU mL⁻¹. Mice showed 100% survival and no viral rebound in brain, spinal cord, and sciatic nerve. NLS induced stronger MHC-I/II-linked cellular immunity and higher RABV G/N-specific IFN-γ spot frequencies than G-mRNA or INV. Conclusions: The dual-antigen NLS vaccine co-delivering G-mRNA and RABV-N via dual-cationic LNPs robustly activates MHC-I/II, rapidly generates high-titer nAb (≥10 IU mL⁻¹ within 1 week), and sustains potent CD8⁺ CTL and CD4⁺ Th responses. A two-dose regimen (days 0 and 21) conferred complete protection, supporting the NLS platform as a next-generation rabies vaccine candidate. Full article

Background Facial clefts are rare congenital malformations, occurring in approximately 1 in 700 live births for cleft lip and palate and fewer than 1 in 100,000 for atypical Tessier clefts. They pose significant diagnostic and surgical challenges. While genetic, vascular, and environmental factors are well documented, growing embryological evidence suggests that the trigeminal nerve may also contribute to craniofacial development. This narrative review explores the association between trigeminal nerve development and facial clefts, aiming to provide a neurodevelopmental perspective with clinical implications, particularly in the context of personalized medicine, where patient-specific neuroanatomical and developmental factors can guide tailored care. Methods A narrative review of embryological, anatomical, and clinical data was conducted. Histological analyses of malformed fetuses and normal human embryos were integrated with published studies. Clinical findings were compared with Paul Tessier’s facial cleft classification and mapped against trigeminal innervation territories. Results Two groups of facial clefts emerged according to the timing of trigeminal disruption. Early embryonic damage (before 10 weeks of gestation) produces superficial epidermal continuity with fibrotic tissue replacing normal deep structures. Later fetal damage results in complete clefts with full tissue discontinuity. The distribution of these clefts corresponds to trigeminal nerve terminal branch territories, supporting the hypothesis that trigeminal innervation exerts trophic effects on craniofacial morphogenesis through neurohormonal signaling. Conclusions Early impairment of trigeminal development may play a pivotal role in the pathogenesis of certain clefts. The spatial and temporal relationship between nerve development and morphogenesis should be considered in classification and surgical planning. However, limitations of this narrative approach include selective literature coverage and lack of quantitative synthesis. Future directions include single-cell transcriptomics, organoid models, and fetal MRI tractography to clarify trigeminal–mesenchyme interactions and inform therapeutic strategies. These advances may foster a personalized medicine approach, enabling more precise prenatal diagnosis, individualized surgical planning, and optimized long-term outcomes. Full article

TRPV4 (transient receptor potential vanilloid 4) is a non-selective, multifunctional cationic channel that is expressed in numerous cells in the body. It can be activated by temperature, mechanical forces, and chemical and biochemical molecules. Functionally, TRPV4 participates in maintaining osmotic homeostasis, blood pressure, and hypoxic preconditioning. As far as we know, the presence of TRPV4 has never been reported in the carotid body despite the overlap that exists between some biological functions of TRPV4 and the physiology of the carotid body. In the present work, immunofluorescence associated with confocal laser microscopy, associated with quantitative analysis (area occupied by immunofluorescence), has been used to examine the occurrence of TRPV4 in the human carotid body. The results demonstrated the presence of TRPV4 in a subpopulation of chemoreceptor type I cells (approximately 65–68%), a subpopulation of type II supporting cells, and in nerve terminals in the human carotid body. Its function, if any, in this multisensory organ must be demonstrated, but it is in line with the functions attributed to the carotid body. Full article

The carotid body is a peripheral chemoreceptor that consists of clusters of chemoreceptive type I cells, glia-like type II cells, afferent and efferent nerves, and sinusoidal capillaries and arterioles. Cells and nerves communicate through reciprocal chemical synapses and electrical coupling that form a “tripartite synapse,” which allows for the process of sensory stimuli within the carotid body involving neurotransmission, autocrine, and paracrine pathways. In this network there are a variety of neurotransmitters and neuromodulators including adenosine 5′-triphosphate (ATP). Carotid body cells and nerve fibre terminals express ATP receptors, i.e., purinergic receptors. Here we used double immunofluorescence associated with laser confocal microscopy to detect the ATP receptor P2X7 and pannexin 1 (an ATP permeable channel) in the human carotid body, as well as the petrosal and cervical sympathetic ganglia. Immunofluorescence for P2X7r and pannexin 1 forms a broad cellular network within the glomeruli of the carotid body, whose pattern corresponds to that of type II cells. Moreover, both P2X7r and pannexin 1 were also detected in nerve profiles. In the petrosal ganglion, the distribution of P2X7r was restricted to satellite glial cells, whereas in the cervical sympathetic ganglion, P2X7r was found in neurons and glial satellite cells. The role of this purinergic receptor in the carotid body, if any, remains to be elucidated, but it probably provides new evidence for gliotransmission. Full article

We examined whether an increase in synaptic activity resulted in an increase in quantal size at the neuromuscular junction (NMJ) of third-instar Drosophila larvae. Spontaneous miniature excitatory postsynaptic currents (mEPSCs) or miniature excitatory postsynaptic potentials (mEPSPs) were recorded before and after nerve stimulation. We found that prolonged (60 s) or brief (1.25 s) nerve stimulation produced an increase in quantal size; this appears to be a general property of these synapses since it was seen at all four muscle fibers (MFs) used in this study. The effect was examined along Is and Ib terminals by expressing GCaMP in the MF membrane and examining postsynaptic Ca²⁺ signals produced by spontaneous transmitter release. The activity-dependent increase in quantal size occurred at both Is and Ib terminals, and the increase in frequency and amplitude of quantal events at individual synaptic boutons was correlated. Both the increase in quantal size and frequency were found to be dependent upon an increase in postsynaptic Ca²⁺, based on studies in which MFs were preinjected with the Ca²⁺ chelator BAPTA (1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid). To examine the effect of postsynaptic activity on glutamate sensitivity, we iontophoresed glutamate pulses at the NMJ and recorded the glutamate-evoked excitatory postsynaptic potentials (gEPSPs). Trains of glutamate pulses produced an increase in gEPSP amplitude; this potentiation was not seen when Ca²⁺ was eliminated from the bath or after inhibiting calmodulin or CaMKII. The activity-dependent increase in quantal size may result from an increase in postsynaptic sensitivity due to activation of CaMKII. Full article

In most vertebrates, males and females display distinct reproductive behaviors. Some fish can change their sexual phenotype at various life stages, which involves alterations in their gonadal sex and changes in their reproductive behavior to align with the new gonadal identity. Although the sex reversal phenomenon in reproductive behavior is well documented, the underlying mechanisms in the brains of these fish remain largely unknown. In the present study, we investigated the roles of the thyroid hormone (triiodothyronine (T3)) in the Mozambique tilapia as a potential regulator of male-specific nest-building behavior and gonadotropin-releasing hormone-3 (GnRH3) neurons, the regulatory neurons of male reproductive behavior, in the terminal nerve (TN) ganglion. T3 injection successfully induced nest-building behavior in mature female fish. T3 injection significantly elevated serum T3 concentrations in treated animals compared with those in controls. Through organotypic culture of brain slices that included the TN region, we demonstrated that T3 could stimulate an increase in the number of GnRH3 neurons, and the effect was inhibited by a thyroid hormone receptor (TR) inhibitor. Additionally, TRβ co-expression was observed in GnRH3 neurons. These findings highlight the crucial roles of T3 and GnRH3 in sex reversal processes within the fish brain. Full article

Background: Brachial plexopathies comprise a diverse array of illnesses with multifactorial etiologies, including trauma, inflammation, neoplasia, and iatrogenic damage, frequently manifesting with nonspecific clinical symptoms. Precise and prompt imaging evaluation is essential for diagnosis, treatment planning, and monitoring. Objective: To equip radiologists with interpretative tools for a systematic assessment of the brachial plexus utilizing advanced imaging modalities, specifically ultrasound (US) and magnetic resonance imaging (MRI), while emphasizing techniques, indications, limitations, and critical radiologic signs for differential diagnosis. Imaging Techniques: This narrative review concentrates on US and MRI. High-frequency linear probes with multiplanar dynamic scans provide US visualization of trunks, cords, and terminal branches in superficial areas. Specialized MRI procedures (T1, T2, STIR, DWI, contrast-enhanced) provide comprehensive evaluation of spinal roots and deep tissues, differentiating preganglionic from postganglionic lesions. A combined US–MRI methodology can enhance diagnostic efficacy. Findings: Ultrasound is excellent for superficial and dynamic assessment, especially in post-traumatic and iatrogenic lesions, while MRI is the gold standard for deep structures and complex disorders. The integration of two modalities enhances lesion identification and treatment direction. Emerging methodologies further enhance diagnostic and prognostic capabilities. Conclusions: The synergistic application of US and MRI, emphasizing nerve injury patterns and muscle denervation indicators, facilitates precise and prompt diagnosis of brachial plexopathies. Standardizing imaging standards and incorporating modern techniques are essential for interdisciplinary, customized patient care. Full article

Contactin-associated protein-like 2 (CASPR2) is a transmembrane protein of the neurexin superfamily, essential for clustering voltage-gated potassium channels, particularly Kv1, at the juxtaparanodal regions of myelinated axons. This precise localisation is essential for maintaining normal axonal excitability and preventing aberrant signal propagation. Autoantibodies targeting CASPR2 have been associated with various neurological syndromes, notably peripheral nerve hyperexcitability (PNH), which presents clinically with neuromyotonia and myokymia. PNH is characterised by distinctive electrophysiological findings, including neuromyotonic discharges, myokymic discharges, and afterdischarges, which provide diagnostic value and insight into underlying pathophysiology. This review explores the mechanisms of anti-CASPR2-associated PNH, focusing on how antibody-mediated disruption of Kv1 channel clustering leads to altered axonal excitability. Current evidence suggests that both the distal and proximal segments of the axon are sites of pathological activity, where impairments in action potential termination and re-entry prevention result in spontaneous, repetitive discharges. While afterdischarges likely originate within the axon, the precise location—whether in the alpha-motoneuron soma or axon—is uncertain. The involvement of spinal inhibitory circuits has also been proposed, though it remains speculative. Understanding the neurophysiological features of anti-CASPR2-associated PNH is essential for improving diagnostic accuracy and guiding treatment strategies. Further research is needed to clarify the mechanisms of CASPR2-related hyperexcitability. Full article

Tissue engineering has the potential to overcome the limitations of using autografts in nerve gap repair, using cellular biomaterials to bridge the gap and support neuronal regeneration. Various types of therapeutic cells could be considered for use in aligned collagen-based engineered neural tissue (EngNT), including Schwann cells and their precursors, which can be derived from human induced pluripotent stem cells (hiPSCs). Using Schwann cell precursors may have practical advantages over mature Schwann cells as they expand readily in vitro and involve a shorter differentiation period. However, the performance of each cell type needs to be tested in EngNT. By adapting established protocols, hiPSCs were differentiated into Schwann cell precursors and Schwann cells, with distinctive molecular profiles confirmed using immunocytochemistry and RT-qPCR. For the first time, both cell types were incorporated into EngNT using gel aspiration–ejection, a technique used to align and simultaneously stabilise the cellular hydrogels. Both types of cellular constructs supported and guided aligned neurite outgrowth from adult rat dorsal root ganglion neurons in vitro. Initial experiments in a rat model of nerve gap injury demonstrated the extent to which the engrafted cells survived after 2 weeks and indicated that both types of hiPSC-derived cells supported the infiltration of host neurons, Schwann cells and endothelial cells. In summary, we show that human Schwann cell precursors promote infiltrating endogenous axons in a model of peripheral nerve injury to a greater degree than their terminally differentiated Schwann cell counterparts. Full article

Background: The primary effect of Botulinum toxin (BoNT) is to cause weakness in the injected muscles by inhibiting the release of acetyl choline from presynaptic nerve terminals. Its effect on sensorimotor integration (SMI) has largely been confined to small studies. The aim of this review is to highlight effect of BoNT on SMI in the context of Parkinson’s disease (PD), Cervical dystonia (CD), and Writer’s cramp (WC). Methods: Using keywords “Botulinum toxin” and “sensorimotor integration” or “Freezing of gait (FOG)” or ‘Tremor”or “Cervical dystonia” or “Parkinson’s disease”, or “Writer’s cramp”, PubMed database was searched for relevant articles supporting our view. The abstracts of all resultant articles (case reports, case series, randomized trials, observational studies) were reviewed to look for evidence of effects of botulinum toxin on SMI. The relevant articles were charted in excel sheet for further full text review. Results: In FOG, chronic BoNT injections may alter central motor patterns with inclusion of alternative striatal systems, cerebellum, and its connections. In tremor, the afferent proprioceptive input may be modified with reduction of intracortical facilitation and increment of intracortical inhibition. In CD, BoNT can restore disorganized cortical somatotrophy, the key pathophysiology behind cervical dystonia. Similarly, in WC, both the deficient sensory system and abnormal reorganization of the sensorimotor cortex may be altered following chronic BoNT injections. Conclusions: There is preliminary evidence that BoNT may modulate SMI in PD, CD, and WC by altering inputs from the muscle spindles in short term and modifying circuits/particular anatomic cerebral cortices in the long term. Properly conducted randomized trials comparing BoNT with placebo or prospective large-scale studies to look for effect on various surrogate markers reflective of changes in SMI should be the next step to confirm these findings. Targeting the system of afferents like spindles and golgi tendon organs in muscles may be a better way of injecting BoNT, with lower amounts of toxin needed and potential for lesser side-effects like weakness and atrophy. However, this needs to be proven in controlled trials. Full article

The aim of this study was to analyze how recombinant rabbit NGF (Nerve Growth Factor) encapsulated in chitosan (rrβNGFch) affects sperm viability, motility, capacitation, acrosome reaction (AR), kinetic traits, and apoptosis after 30 min and 2 h of storage. Specific intracellular signaling pathways associated with either cell survival, such as protein kinase B (AKT) and extracellular signal-regulated kinases 1/2 (ERK1/2), or programmed cell death, such as c-Jun N-terminal kinase (JNK), were also analyzed. The results confirmed the effect of rrβNGFch on capacitation and AR, whereas a longer storage time (2 h) decreased all qualitative sperm traits. AKT and JNK did not show treatment-dependent activation and lacked a correlation with functional traits, as shown by ERK1/2. These findings suggest that rrβNGFch may promote the functional activation of sperm cells, particularly during early incubation. The increase in capacitation and AR was not linked to significant changes in pathways related to cell survival or death, indicating a specific action of the treatment. In contrast, prolonged storage negatively affected all sperm parameters. ERK1/2 activation correlated with capacitation, AR, and apoptosis, supporting its role as an NGF downstream mediator. Further studies should analyze other molecular mechanisms of sperm and the potential applications of NGF in assisted reproduction. Full article

The agents of prion diseases have the capacity to efficiently infect susceptible hosts by peripheral routes and to project to clinical target areas of the central nervous system (CNS) via peripheral nerves. Understanding the process of prion spread from the site of infection to the CNS may allow us to identify novel therapeutic strategies. To investigate the mechanism involved in the intranerval transit of 263K scrapie prions in golden Syrian hamsters (GSHs), we transected the sciatic nerve at increasing times post-footpad injection and recorded the incubation periods as estimates of the efficiency of infection. We calculated that intranerval transit of this strain of scrapie is at least 10 times faster than previously reported and may reach 50 mm/day, similar to other neurotropic viruses. By in vivo exposure/injection of sciatic nerves to 263K infectivity, we have also shown that prion entry likely occurs via nerve terminals rather than by direct contact with the sciatic nerve. Application of this experimental approach in other forms of prion diseases could allow verification of the timing of neuroinvasion, a relevant parameter for the definition of therapeutic interventions. Full article

Opioids are among the most effective drugs for treating moderate to severe pain. Unfortunately, opioid use, even short-term, can lead to addiction, tolerance, overdose, and respiratory depression. Therefore, efforts to design and develop novel compounds that would retain analgesic activity while reducing side effects continue unabated. The present study was designed to investigate the respiratory and cardiovascular effects of the hybrid peptide LENART01, which has evidenced potent antinociceptive and antimicrobial activity. This hybrid peptide, composed of N-terminally located dermorphin and C-terminal modified ranatensin pharmacophore, was tested in vivo in anesthetized rats. The main effect of LENART01 was apnea in 70% of examined animals, sighing, and a significant increase in blood pressure. Interestingly, the hybrid induced sighs less frequently than ranatensin, and apnea dependent on vagus nerve mu opioid receptor activation much less frequently and less intensely than dermorphin itself. This shows that LENART01 is a safer opioid system-related agent as compared to dermorphin for its prospective use in the treatment of pain. Full article