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Advanced Neurology

REVIEW ARTICLE
Neurodevelopmental disorders and the role

of PSD-95: Understanding pathways and
pharmacological interventions

Gerardo Medina * and Alex E. MacKenzie 1,2,3
1
1 Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
2 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa; Ottawa,
Ontario, Canada
3 Eric Poulin Center for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ontario,
Canada

Abstract

Neurodevelopmental disorders (NDDs) are often linked to disruption in brain
development and present challenges for affected individuals in achieving their
cognitive, emotional, and motor developmental milestones. NDDs encompass a
spectrum of conditions, including autism spectrum disorder (ASD), schizophrenia
(SCZ), attention-deficit hyperactivity disorder (ADHD), and epilepsy. The unequivocal
diagnosis of an NDD is often challenging due to overlapping signs and symptoms
across different conditions. Synaptic plasticity, the activity-driven modification of
synaptic strength and efficacy, plays a crucial role in brain network formation and
*Corresponding author: organization and is frequently altered in NDDs. Here, we explore the multifaceted
Gerardo Medina roles of postsynaptic density-95 kDa (PSD-95) in NDDs. Psd-95 is a scaffolding
(gmedina@cheo.on.ca) protein belonging to the membrane-associated guanylate kinases (MAGUKs) family,
Citation: Medina G, MacKenzie AE. located at the core of synapses, and is central to synaptic plasticity. Dysregulation
Neurodevelopmental disorders and of PSD-95 is linked to various neuropsychiatric disorders. In SCZ, decreased PSD-95
the role of PSD-95: Understanding
pathways and pharmacological expression affects synaptic plasticity, thereby impacting learning and memory. Genes
interventions. Adv Neuro. associated with ASD interact with PSD-95, and its removal in mice leads to ASD-like
2024;3(1):2095. behavioral abnormalities. Furthermore, PSD-95 is implicated in ADHD, where its
https://doi.org/10.36922/an.2095 modulation influences neurotransmission. Medications used in NDD treatment,
Received: October 24, 2023 such as antipsychotic drugs and selective serotonin reuptake inhibitors (SSRIs), can
Accepted: December 27, 2023 alter PSD-95 levels, potentially influencing synapse formation. Alpha-2 adrenergic
agonists might enhance synaptic integrity by impacting PSD-95. Alternative
Published Online: March 4, 2024 pharmacotherapies such as memantine, allopurinol, and ketamine, all influencing
Copyright: © 2024 Author(s). PSD-95 to a certain extent, hold promise in managing NDDs. Understanding the
This is an Open-Access article role of PSD-95 in these disorders can deepen our biological comprehension and
distributed under the terms of the
Creative Commons Attribution pave the way for targeted therapies. Specifically, exploring how PSD-95 affects
License, permitting distribution, synaptic plasticity and dendritic spine development could uncover opportunities
and reproduction in any medium, for repurposing drugs to treat NDDs associated with mutations in the DLG4 gene
provided the original work is
properly cited. encoding PSD-95.
Publisher’s Note: AccScience
Publishing remains neutral with Keywords: PSD-95; DLG4; Neurodevelopmental disorder; Pharmacotherapy; N-methyl-d-
regard to jurisdictional claims in
published maps and institutional aspartate receptor; Autism
affiliations.

Volume 3 Issue 1 (2024) 1 https://doi.org/10.36922/an.2095