Neurodevelopmental disorders and the role of PSD-95: Understanding pathways and pharmacological interventions

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 organization and is frequently altered in NDDs. Here, we explore the multifaceted roles of postsynaptic density-95 kDa (PSD-95) in NDDs. Psd-95 is a scaffolding protein belonging to the membrane-associated guanylate kinases (MAGUKs) family, located at the core of synapses, and is central to synaptic plasticity. Dysregulation of PSD-95 is linked to various neuropsychiatric disorders. In SCZ, decreased PSD-95 expression affects synaptic plasticity, thereby impacting learning and memory. Genes associated with ASD interact with PSD-95, and its removal in mice leads to ASD-like behavioral abnormalities. Furthermore, PSD-95 is implicated in ADHD, where its modulation influences neurotransmission. Medications used in NDD treatment, such as antipsychotic drugs and selective serotonin reuptake inhibitors (SSRIs), can alter PSD-95 levels, potentially influencing synapse formation. Alpha-2 adrenergic agonists might enhance synaptic integrity by impacting PSD-95. Alternative pharmacotherapies such as memantine, allopurinol, and ketamine, all influencing PSD-95 to a certain extent, hold promise in managing NDDs. Understanding the role of PSD-95 in these disorders can deepen our biological comprehension and pave the way for targeted therapies. Specifically, exploring how PSD-95 affects synaptic plasticity and dendritic spine development could uncover opportunities for repurposing drugs to treat NDDs associated with mutations in the DLG4 gene encoding PSD-95.