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Advanced Neurology PSD-95 in neurodevelopmental disorders

an increase in PSD-95 expression, resulting in elevated the maturation of glutamatergic synapses. This reduction,
levels of AMPAR and a corresponding augmentation possibly a response to excessive neuronal excitability,
in the number and density of dendritic spines, thereby might affect the capacity of neurons to create and retain
promoting synapse formation. These findings indicate memories. Furthermore, a significant decrease in PSD-
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the pivotal role of PSD-95 in regulating synaptic plasticity 95 mRNA and protein levels is observed in the dorsolateral
mechanisms such as LTP and long-term depression (LTD) and dorsomedial prefrontal cortices of postmortem samples
through its role in AMPA receptor scaffolding. In addition, from individuals with SCZ, 16,30 suggesting a connection
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synaptic activity promotes PSD-95 depalmitoylation between PSD-95 dysfunction and SCZ.
and activates glycogen synthase kinase-3 beta (GSK-3β), Notably, PSD-95 is known for its involvement in a
leading to the phosphorylation of PSD-95 at tyrosine 19 network of interactions with proteins associated with
(T19). Phosphorylation at T19 prompts calcium-bound ASD, including SHANK, HOMER, neuroligin, and FMRP
calmodulin to interact with PSD-95 and antagonizes (fragile X -mental retardation protein). 16,31 Mouse studies
palmitoylation, promoting PSD-95 release from the have demonstrated that DLG4 ablation leads to increased
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PSD. Here, we seek to outline the involvement of PSD- repetitive behavior, decreased vocalization, and irregular
95 in NDDs and explore the potential pharmacological social interactions, all of which are hallmarks of ASD.
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treatments targeting NDDs in the management of PSD-95. Likewise, DLG4 has been recently identified in a genetic
2. PSD-95 and NDDs study as a potential gene that could be implicated in cases
of ID. 16,33 In addition, disrupted PSD-95 has been linked to
Mutations in the PSD-95 encoding gene, known by its other neurological conditions such as Alzheimer’s disease
unwieldy name as discs large MAGUK scaffold protein (AD). In AD, the relocation of PSD-95 from dendrites
4 gene (DLG4), give rise to DLG4-related synaptopathy, to neuronal soma and accumulation in Hirano bodies,
a condition characterized by intellectual disability (ID), protein aggregates associated with neurodegenerative
global developmental delay (DD), ASD, ADHD, epilepsy, disorders, have been proposed to cause damage at the
hypotonia, and movement disorders. The majority postsynaptic level. A recent study demonstrated that
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of DLG4 mutations identified in the approximately preventing depalmitoylation increased the levels of PSD-95
100 individuals are severe and likely null, resulting in at synapses, thereby guarding them against the toxic effects
haploinsufficiency with reduced PSD-95 levels, thus of amyloid-β peptides, a key element in AD pathology.
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contributing to the disorder, also known as SHINE This finding indicates that pharmacological inhibition of
syndrome (sleep disturbances, hypotonia, intellectual depalmitoylation, which enhances PSD-95 clustering at
disabilities, neurological disorders, and epilepsy). 23-25 synapses, might hold promise as a potential therapeutic
These affected individuals demonstrate autistic traits and strategy for treating AD.
experience regression in motor and language skills, along
with instances of psychosis, although psychosis is not 2.1. PSD-95 and SCZ
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considered a defining characteristic of this condition. 24,26 SCZ is a chronic mental disorder that typically manifests
PSD-95 undergoes various posttranslational during adolescence or early adulthood and is believed to
modifications (PTMs) known to impact synaptic plasticity, stem from molecular and biochemical changes during
dendritic spine development, the function of glutamate development. Throughout development, the levels of
receptors, and their positioning in the postsynaptic area. PSD-95 protein increase until late adolescence and
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LTP and LTD are critical processes in the maturation early adulthood, coinciding with the growth of synaptic
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of dendritic spines, and alterations in the PSD could density in the human PFC. However, as outlined below,
potentially hinder the essential spine formation process, individuals with SCZ exhibit notable vulnerability in
leading to synaptic disorders. Thus, dysregulation of PSD-95, potentially disrupting typical spine growth and
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PSD-95 could disrupt the trafficking and functioning of synaptic function. Researchers have identified increased
NMDA and AMPA receptors, diminishing spine density alterations in several genes encoding proteins, such as
and maturation, particularly in regions like the prefrontal neuregulin, dysbindin, and neuroligin, resulting in NMDA
cortex (PFC). For instance, Coley and Gao noted that a dysfunction in SCZ. There is a possibility that an abnormal
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deficiency in PSD-95 disrupts the balance between NMDAR interaction between PSD-95 and NMDAR (Figure 2B)
and AMPAR and weakens glutamatergic transmission might contribute to the maladaptive neurodevelopmental
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in the medial PFC. This disruption could delay synaptic changes observed in SCZ.
plasticity, consequently impacting learning and memory. Neuroanatomical studies of SCZ patients reveal
In a separate study, recurrent seizures in infant mice were structural irregularities in specific brain regions. These
found to decrease PSD-95 levels, which interfered with include an overall decrease in brain volume and reduced

Volume 3 Issue 1 (2024) 4 https://doi.org/10.36922/an.2095