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Advanced Neurology PSD-95 in neurodevelopmental disorders

cortical gray matter in regions such as the dorsolateral forms connections with proteins associated with SCZ,
PFC, superior temporal gyrus, and limbic areas (such such as DISC1 and neuroligin, thereby influencing protein
as the hippocampal formation and anterior cingulate complexes crucial for forming dysfunctional synapses,
cortex). Some reports indicate a reduction in neuronal which could also play a role in SCZ (as shown in Table 1). 16,45
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count and dendritic spine densities in the hippocampus Furthermore, disruptions in ErbB4 signaling, closely linked
and dorsolateral PFC, although this finding is not to SCZ, destabilize AMPAR and NMDAR at the postsynaptic
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universally observed. For instance, in individuals with membrane. Similarly, SAP-102 and neurofilament light
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SCZ, there is a documented reduction in PSD-95 gene peptide (NF-L), two molecules similar to PSD-95 involved
expression within the PFC (Table 1). Interestingly, in
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the same population, PSD-95 mRNA and protein levels in the trafficking and stabilization of NMDARs in cell
have increased in the occipital cortex and thalamus. membranes, have also been suggested to be involved in
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40
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The disruption of glutamate receptor regulation observed the pathophysiology of SCZ. These findings reinforce the
in SCZ involves changes in key intracellular molecules notion of potential dysfunction in the glutamatergic system
integral to the signaling of glutamate receptors, including in this psychiatric disorder while establishing connections
PSD-95. PSD-95 deficiency can potentially contribute between the receptor and downstream signaling molecules
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to synaptic loss by altering the synapse balance between within the postsynaptic cell. 47
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NMDAR and AMPAR. 43,44 In addition, PSD-95 directly 2.2. PSD-95 and autism
Table 1. Neurodevelopmental disorders associated with Autism, an NDD characterized by behavioral abnormalities,
PSD‑95 dysfunction including repetitive actions, limited vocal communication,
and unusual social interactions, is thought to be related, at
Neurodevelopmental Association with PD‑95 least in part, to synaptic dysfunction. Genomic analysis
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disorder and exome sequencing studies of autism patients have
Schizophrenia • PSD‑95 may have an abnormal revealed genetic mutations in synaptic proteins, including
interaction with NMDAR, contributing to 49-51
neurodevelopmental changes in SCZ. 41 PSD-95 (Table 1). These data suggest that reduced PSD-
• Reduced PSD‑95 gene expression in the 95 might contribute to autism. 16
prefrontal cortex. 39
• PSD‑95 links with proteins linked to SCZ Autism may result from dysregulation of the complex
(DISC1, neuroligin), affecting synapse interplay of macromolecules within the PSD, such as
formation. 46 SHANK, HOMER, FMRP, and neuroligin. Intriguingly,
Autism spectrum • Genetic mutations in synaptic proteins like these molecules interact directly or indirectly with PSD-95,
disorder PSD-95 were observed in autism patients. 49 potentially influencing synaptic structure and function. 52,53
• Complex effects on dendritic spines and For instance, PSD-95 significantly recruits the adhesive
synaptic gene expression in PSD-95 null molecule neuroligin to excitatory synapses during brain
mice. 32
• Increased PSD‑95 in rats exposed prenatally development. The PSD-95-neuroligin partnership fosters
to valproic acid as a model of ASD. 50 connections between neurons and promotes synaptic
• Different autism‑related genes implicated maturity. An excess of this partnership might disrupt
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in PSD-95-mediated deficits in synapse typical synaptic development. In addition, PSD-95’s
elimination. 51 association with fragile X syndrome, due to FMRP
ADHD • PSD‑95 and its direct role in ADHD are not mutations, leads to decreased PSD-95 degradation and
yet well established.
• PSD‑95 may play a role in ADHD by consequently hampers synaptic pruning. 14,55 For instance,
−/−
influencing neurotransmitter systems such homozygous PSD-95 (DLG4 ) mice display a complex
as dopamine, serotonin, glutamate, and range of symptoms similar to those observed in autistic
GABA. 58,62 individuals. These symptoms include heightened repetitive
• Role of PSD‑95 in the modulation of behaviors, unusual communication patterns, impaired
NMDAR and dopamine receptor signaling. 63
• A hypodopaminergic state in ADHD might social interactions, compromised motor coordination,
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lead to increased NMDAR and AMPAR and increased responses linked to stress and anxiety. In
activity, resulting in elevated glutamate addition, these mice exhibit altered dendritic spine shapes
output. 65 in the amygdala and disrupted expression of synaptic
Abbreviations: ADHD: Attention-deficit hyperactive disorder; genes in the forebrain, some associated with autism.
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AMPAR: α-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic This observation suggests that DLG4 may play a role in
acid receptors; ASD: autism spectrum disorder;
NMDAR: N-methyl-d-aspartic acid receptors; PSD-95: Postsynaptic specific behavioral abnormalities in NDDs like autism.
density-95; SCZ: schizophrenia. Furthermore, in a rat model of ASD, male rats exposed to

Volume 3 Issue 1 (2024) 5 https://doi.org/10.36922/an.2095