Biological Mechanisms in the Treatment of Neuropsychiatric Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 31 July 2025 | Viewed by 6235

Special Issue Editors


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Guest Editor
EuMentis Therapeutics, Newton, MA, USA
Interests: neurodevelopmental conditions; rare neurological disease; molecular mechanisms of novel CNS treatments; precision medicine in neuropsychiatry; clinical trials methodology

E-Mail Website
Guest Editor
MindImmune Therapeutics, Inc., The George & 6 Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA
Interests: NMDA; europharmacology

Special Issue Information

Dear Colleagues,

Diseases affecting the nervous system are the leading cause of overall disease burden in the world, affecting 3.4 billion persons. Although research in basic neuroscience has thrived for several decades, interest in applied neurosciences—developing new therapies—has lagged behind until the recent few years, when we have seen a resurgence of commitment to therapeutics development. The urgent need for progress in the understanding of molecular, circuit-related, and genetic causal factors for serious neurological and psychiatric conditions is again attracting the considerable governmental and private investments needed to progress an empirically founded idea into a successful therapeutic.

This Special Issue of Cells focuses on novel methodologies, promising cellular and molecular mechanisms, and treatments that offer hope for patients with a range of disorders and diseases for which there is a considerable need for safer, better tolerated, more effective medical treatments. Successful clinical trials require valid, quantitative outcome measures that are sensitive to the physiologic and biological features of the disease under study. However, limitations in outcome assessment methodology are believed to have hampered the discovery of effective treatments. Advances in the understanding of the molecular mechanisms of genetic diseases have ushered in a renaissance of interest in rare neurological conditions for which, unlike most neuropsychiatric conditions, the pathology is well-characterized and can thus inform rational therapeutic development. The application of precision medicine approaches within highly heterogeneous neuropsychiatric conditions is being pursued as a potentially more successful strategy where the “one size fits all” approach has clearly failed. Moreover, novel methods for preclinical drug screening, which are more relevant to human biology, have come to the fore as potentially more predictive of human safety outcomes.

With this selection of ongoing work in the field, we hope to encourage an optimistic mindset toward the possibility that the following decade will see the creation of many new and better therapies to improve the lives of millions of people with these conditions.

Dr. Randall D Marshall
Dr. Frank S. Menniti
Guest Editors

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Keywords

  • neurodevelopmental conditions
  • rare neurological disease
  • molecular mechanisms of novel CNS treatments
  • precision medicine in neuropsychiatry
  • organoids
  • molecular mechanisms of effective treatments

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Published Papers (5 papers)

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Research

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23 pages, 4274 KiB  
Article
Investigation of the Roles of the Adenosine A(2A) and Metabotropic Glutamate Receptor Type 5 (mGlu5) Receptors in Prepulse Inhibition and CREB Signaling in a Heritable Rodent Model of Psychosis
by Anthony M. Cuozzo, Loren D. Peeters, Cristal D. Ahmed, Liza J. Wills, Justin T. Gass and Russell W. Brown
Cells 2025, 14(3), 182; https://doi.org/10.3390/cells14030182 - 24 Jan 2025
Cited by 1 | Viewed by 997
Abstract
The metabotropic glutamate receptor type 5 (mGlu5) and adenosine A(2A) receptor form a mutually inhibitory heteromer with the dopamine D2 receptor, where the activation of either mGlu5 or A(2A) leads to reduced D2 signaling. This study investigated whether a mGlu5-positive allosteric modulator (PAM) [...] Read more.
The metabotropic glutamate receptor type 5 (mGlu5) and adenosine A(2A) receptor form a mutually inhibitory heteromer with the dopamine D2 receptor, where the activation of either mGlu5 or A(2A) leads to reduced D2 signaling. This study investigated whether a mGlu5-positive allosteric modulator (PAM) or an A(2A) agonist treatment could mitigate sensorimotor gating deficits and alter cyclic AMP response element-binding protein (CREB) levels in a rodent neonatal quinpirole (NQ) model of psychosis. F0 Sprague–Dawley rats were treated with neonatal saline or quinpirole (1 mg/kg) from postnatal day 1 to 21 and bred to produce an F1 generation. F1 offspring underwent prepulse inhibition (PPI) testing from postnatal day 44 to 48 to assess sensorimotor gating. The rats were treated with mGlu5 PAM 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) or A(2A) agonist CGS21680. Rats with at least one NQ-treated parent showed PPI deficits, which were alleviated by both CDPPB and CGS21680. Sex differences were noted across groups, with CGS21680 showing greater efficacy than CDPPB. Additionally, CREB levels were elevated in the nucleus accumbens (NAc), and both CDPPB and CGS21680 reduced CREB expression to control levels. These findings suggest that targeting the adenosinergic and glutamatergic systems alleviates sensorimotor gating deficits and abnormal CREB signaling, both of which are associated with psychosis. Full article
(This article belongs to the Special Issue Biological Mechanisms in the Treatment of Neuropsychiatric Diseases)
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Review

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21 pages, 1425 KiB  
Review
Epigenetics and Gut Microbiota in the Pathogenesis and Treatment of Bipolar Disorder (BD)
by Shabnam Nohesara, Hamid Mostafavi Abdolmaleky, Ahmad Pirani and Sam Thiagalingam
Cells 2025, 14(14), 1104; https://doi.org/10.3390/cells14141104 - 18 Jul 2025
Viewed by 291
Abstract
Bipolar disorder (BD) is a multifactorial mental disease with a prevalence of 1–5% in adults, caused by complex interactions between genetic and environmental factors. Environmental factors contribute to gene expression alterations through epigenetic mechanisms without changing the underlying DNA sequences. Interactions between the [...] Read more.
Bipolar disorder (BD) is a multifactorial mental disease with a prevalence of 1–5% in adults, caused by complex interactions between genetic and environmental factors. Environmental factors contribute to gene expression alterations through epigenetic mechanisms without changing the underlying DNA sequences. Interactions between the gut microbiota (GM) and diverse external factors, such as nutritional composition, may induce epigenetic alterations and increase susceptibility to BD. While epigenetic mechanisms are involved in both the pathogenesis of BD and drug treatment responses, epigenetic marks could be employed as predictors and indicators of drug response. This review highlights recent studies on the potential role of epigenetic aberrations in the development and progression of BD. Next, we focus on drug response-related alterations in the epigenetic landscape, including DNA methylation, histone modifications, and non-coding RNAs. Afterward, we delve into the potential roles of GM-induced epigenetic changes in the pathogenesis of BD and GM-based therapeutic strategies aimed at improving BD outcomes through epigenetic modifications. We also discuss how BD drugs may exert beneficial effects through modulation of the GM and the epigenome. Finally, we consider future research strategies that could address existing challenges. Full article
(This article belongs to the Special Issue Biological Mechanisms in the Treatment of Neuropsychiatric Diseases)
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26 pages, 959 KiB  
Review
Autophagy and Alzheimer’s Disease: Mechanisms and Impact Beyond the Brain
by Zaw Myo Hein, Thirupathirao Vishnumukkala, Barani Karikalan, Aisyah Alkatiri, Farida Hussan, Saravanan Jagadeesan, Mohd Amir Kamaruzzaman, Muhammad Danial Che Ramli, Che Mohd Nasril Che Mohd Nassir and Prarthana Kalerammana Gopalakrishna
Cells 2025, 14(12), 911; https://doi.org/10.3390/cells14120911 - 16 Jun 2025
Viewed by 905
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by neuronal loss, cognitive decline, and pathological hallmarks such as amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. Recent evidence highlights autophagy as a pivotal mechanism in cellular homeostasis, mediating the clearance of misfolded proteins [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by neuronal loss, cognitive decline, and pathological hallmarks such as amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. Recent evidence highlights autophagy as a pivotal mechanism in cellular homeostasis, mediating the clearance of misfolded proteins and damaged organelles. However, impaired autophagy contributes significantly to AD pathogenesis by disrupting proteostasis, exacerbating neuroinflammation, and promoting synaptic dysfunction. This review aims to scrutinize the intricate relationship between autophagy dysfunction and AD progression, explaining key pathways including macroautophagy, chaperone-mediated autophagy (CMA), and selective autophagy processes such as mitophagy and aggrephagy. This further extends the discussion beyond the central nervous system, evaluating the role of hepatic autophagy in Aβ clearance and systemic metabolic regulation. An understanding of autophagy’s involvement in AD pathology via various mechanisms could give rise to a novel therapeutic strategy targeting autophagic modulation to mitigate disease progression in the future. Full article
(This article belongs to the Special Issue Biological Mechanisms in the Treatment of Neuropsychiatric Diseases)
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25 pages, 1508 KiB  
Review
Modulating Cognition-Linked Histone Acetyltransferases (HATs) as a Therapeutic Strategy for Neurodegenerative Diseases: Recent Advances and Future Trends
by Huong Anh Mai, Christina M. Thomas, Gu Gu Nge and Felice Elefant
Cells 2025, 14(12), 873; https://doi.org/10.3390/cells14120873 - 10 Jun 2025
Viewed by 780
Abstract
Recent investigations into the neuroepigenome of the brain are providing unparalleled understanding into the impact of post-translational modifications (PTMs) of histones in regulating dynamic gene expression patterns required for adult brain cognitive function and plasticity. Histone acetylation is one of the most well-characterized [...] Read more.
Recent investigations into the neuroepigenome of the brain are providing unparalleled understanding into the impact of post-translational modifications (PTMs) of histones in regulating dynamic gene expression patterns required for adult brain cognitive function and plasticity. Histone acetylation is one of the most well-characterized PTMs shown to be required for neuronal function and cognition. Histone acetylation initiates neural circuitry plasticity via chromatin control, enabling neurons to respond to external environmental stimuli and adapt their transcriptional responses accordingly. While interplay between histone acetylation and deacetylation is critical for these functions, dysregulation during the aging process can lead to significant alterations in the neuroepigenetic landscape. These alterations contribute to impaired cognitive functions, neuronal cell death, and brain atrophy, all hallmarks of age-related neurodegenerative disease. Significantly, while age-related generation of DNA mutations remains irreversible, most neuroepigenetic PTMs are reversible. Thus, manipulation of the neural epigenome is proving to be an effective therapeutic strategy for neuroprotection in multiple types of age-related neurodegenerative disorders (NDs) that include Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). Here, we highlight recent progress in research focusing on specific HAT-based neuroepigenetic mechanisms that underlie cognition and pathogenesis that is hallmarked in age-related NDs. We further discuss how these findings have potential to be translated into HAT-mediated cognitive-enhancing therapeutics to treat these debilitating disorders. Full article
(This article belongs to the Special Issue Biological Mechanisms in the Treatment of Neuropsychiatric Diseases)
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41 pages, 4966 KiB  
Review
Neurobiological Mechanisms Underlying Psychological Dysfunction After Brain Injuries
by Prashin Unadkat, Tania Rebeiz, Erum Ajmal, Vincent De Souza, Angela Xia, Julia Jinu, Keren Powell and Chunyan Li
Cells 2025, 14(2), 74; https://doi.org/10.3390/cells14020074 - 8 Jan 2025
Viewed by 2407
Abstract
Despite the presentation of similar psychological symptoms, psychological dysfunction secondary to brain injury exhibits markedly lower treatment efficacy compared to injury-independent psychological dysfunction. This gap remains evident, despite extensive research efforts. This review integrates clinical and preclinical evidence to provide a comprehensive overview [...] Read more.
Despite the presentation of similar psychological symptoms, psychological dysfunction secondary to brain injury exhibits markedly lower treatment efficacy compared to injury-independent psychological dysfunction. This gap remains evident, despite extensive research efforts. This review integrates clinical and preclinical evidence to provide a comprehensive overview of the neurobiological mechanisms underlying neuropsychological disorders, focusing on the role of key brain regions in emotional regulation across various forms of brain injuries. It examines therapeutic interventions and mechanistic targets, with the primary goal of identifying pathways for targeted treatments. The review highlights promising therapeutic avenues for addressing injury-associated psychological dysfunction, emphasizing Nrf2, neuropeptides, and nonpharmacological therapies as multi-mechanistic interventions capable of modulating upstream mediators to address the complex interplay of factors underlying psychological dysfunction in brain injury. Additionally, it identifies sexually dimorphic factors as potential areas for further exploration and advocates for detailed investigations into sex-specific patterns to uncover additional contributors to these disorders. Furthermore, it underscores significant gaps, particularly the inadequate consideration of interactions among causal factors, environmental influences, and individual susceptibilities. By addressing these gaps, this review provides new insights and calls for a paradigm shift toward a more context-specific and integrative approach to developing targeted therapies for psychological dysfunction following brain injuries. Full article
(This article belongs to the Special Issue Biological Mechanisms in the Treatment of Neuropsychiatric Diseases)
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