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Advanced Neurology PSD-95 in neurodevelopmental disorders

synapses during brain development is attributed to its mobility of AMPARs is associated with the depletion of
interactions and functional implications with NMDAR PSD-95, both within the nanocluster and throughout the
and AMPAR. Notably, PSD-95 is essential in stabilizing PSD. 20
NMDAR at the postsynaptic membrane and is involved
in synapse formation, microtubule network dynamics, PSD-95 is intricately involved in glutamatergic
axonal elongation, and cell adhesion. 16,18 PSD-95, in its transmission, synaptic plasticity, and the
palmitoylated form, organizes in nanoclusters within structural development of dendritic spines during
the PSD (Figure 2A). These nanoclusters, approximately neurodevelopment. 12,16 For instance, PSD-95 directly
100 nm in diameter with an enrichment factor of 1.8, are binds to stargazin/TARPs, which in turn interact with
critical organizers of AMPAR. Interestingly, increased the AMPAR subunit GluR1. This interaction leads to
21
19
A B

C D

Figure 2. PSD-95 and neurodevelopmental diseases. (A) PSD-95 protein connections in the postsynaptic density. Postsynaptic density-95 (PSD-95)
interacts directly and indirectly with many macromolecules at the PSD. PDZ domains of PSD-95 bind directly to N-methyl-d-aspartic acid receptors
(NMDAR). PSD-95 also interacts with ADAM22, neuroligin, and K channels. PSD-95 has indirect interactions with α-amino-3-hydroxy-5-methyl-4-
+
isox-azoleproprionic acid receptors (AMPAR) through stargazin. (B) PSD-95 and schizophrenia (SCZ). Elevated changes in multiple genes that code for
proteins lead to NMDA dysfunction in SCZ. PSD-95 establishes direct connections with SCZ-associated proteins such as DISC1 and neuroligin, thus
impacting vital protein complexes essential for formation. (C) PSD-95 and autism spectrum disorder (ASD). Notably, various genes associated with
autism, such as fragile X mental retardation 1 (FMRP), have been linked to the breakdown of PSD-95 and the removal of synapses. This suggests that PSD-
95-related problems in synapse removal may contribute to autism in cases with different genetic origins. (D) PSD-95 and attention-deficit hyperactivity
disorder (ADHD). ADHD could lead to a disrupted NMDAR and AMPAR at the membrane, resulting in a loss or deficient amount of PSD-95.
Abbreviations: GK: Guanylate kinase; GKAP: Guanylate kinase-associated protein; PDZ: PSD-95/disks large/zona occluden; SH3: Src homology 3.

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