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Advanced Neurology PSD-95 in neurodevelopmental disorders

SCZ. The consideration of memantine for off-label use levels in the cerebellum, hippocampus, and striatum.
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in psychiatric disorders is based on the hypothesis that Finally, the precise regulation of cytosolic calcium (Ca )
2+
glutamatergic dysfunction plays a role in the pathogenesis increases, and quick Ca signal termination is required to
2+
of SCZ. Initial case reports have tested memantine as control synaptic communication and neurotransmitter
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an adjunctive therapy alongside the atypical antipsychotic release, regulating various essential CNS processes. This
clozapine in individuals with catatonic SCZ, leading to Ca -dependent signaling is affected by ketamine and may
2+
swift clinical improvement. At present, the role of PSD- mediate at least some of the psychotomimetic effects that can
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95 modulation by memantine in these clinically beneficial be observed with the drug. 120
effects has not been thoroughly investigated. However,
since the connection between memantine and PSD-95 lies 4. Conclusion and future perspectives
in their roles in synaptic transmission and plasticity, it can NDDs, encompassing ASD, SCZ, ADHD, and epilepsy,
be hypothesized that an interaction between memantine significantly affect cognitive, emotional, and motor
and PSD-95 with NMDAR might contribute to some of the developmental milestones. The pathophysiology of
observed clinical benefits. NDDs often involves disruption in synaptic plasticity
and dysregulated PSD-95, whose deficiency disrupts the
3.4.2. Allopurinol balance between NMDAR and AMPAR. Consequently, the
Allopurinol functions as a xanthine oxidase inhibitor. resulting attenuation of glutamatergic transmission affects
Combined with its active metabolite oxypurinol, it serves learning and memory in the PFC and has been implicated
as a scavenger for harmful hydroxyl free radicals and in all NDDs.
binds to iron, not bound to proteins (pro-radical iron). In addition, altered PSD-95 protein levels have been
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Interestingly, elevated levels of xanthine oxidase have observed in the PFC of schizophrenic patients, reinforcing
been observed in individuals with depression, and its the role of PSD-95 dysfunction in the pathology of the
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involvement in depressive disorders has been established disease. In ASD, genomic screenings have identified
through clinical and experimental research. 114,115 Prickaerts genetic mutations in synaptic proteins, including PSD-95,
et al. discovered that the administration of allopurinol which contribute to the observed behavioral abnormalities
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to underweight piglets led to increased protein expression and altered dendritic spine morphology.
of PSD-95 and BDNF. This finding is significant because
a reduced BDNF in the brain is associated with stress and While the direct role of PSD-95 in ADHD pathology
depressive symptoms. Moreover, BDNF can enhance the remains incompletely established, indirect associations are
size of PSD-95 clusters in dendritic spines and overall plausible due to disruptions in various neurotransmitter
PSD-95 levels in dendrites. Allopurinol has been shown systems and brain regions associated with ADHD.
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to improve neuronal plasticity; however, the precise Specifically, neurotransmitter systems, such as dopamine,
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mechanism by which allopurinol increases PSD-95 levels serotonin, glutamate, and GABA, have been implicated in
ADHD, and PSD-95 may mediate their effects on synaptic
remains to be investigated.
plasticity.
3.4.3. Ketamine Regarding potential therapeutic applications, drugs
The anesthetic NMDAR antagonist ketamine is generally well targeting PSD-95 and its associated signaling pathways hold
tolerated and confers clinical benefits to depressive patients promise in treating NDDs. For instance, antipsychotics,
who do not respond to conventional antidepressants, acting SSRIs, α2-ARs, and alternative treatments such as
within hours rather than weeks, as is typically observed memantine, allopurinol, and ketamine have been studied
with more traditional antidepressants. At a cellular level, for their effects on synaptic function and PSD-95 levels.
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ketamine temporarily increases the number and activity of These pharmacotherapies may influence synaptic plasticity
synaptic connections by promoting glutamate bursts through and dendritic spine morphology, offering opportunities
the disinhibition of GABA interneurons. Since NMDAR to improve cognitive function and alleviate behavioral
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drives the tonic firing of these GABA interneurons, ketamine symptoms in patients with NDDs.
can enter and block channel activity when these receptors are Future research should focus on unraveling the complex
in an active, open-channel state. It has been shown that the interactions between PSD-95 and its associated proteins
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interaction of PSD-95 and NMDAR2A regulates synaptic in NDDs. Investigating the precise mechanisms by which
development, and the presence of the PSD-95/NMDAR2A PSD-95 influences synaptic plasticity and dendritic spine
complex suggests that NMDAR-containing synapses are morphogenesis is critical for expanding opportunities
maturing. Rats receiving an intraperitoneal injection dose of for drug repurposing to treat NDDs related to DLG4
ketamine (30 mg/kg) showed increased PSD-95/NMDAR2A mutations such as SHINE syndrome. 23

Volume 3 Issue 1 (2024) 11 https://doi.org/10.36922/an.2095