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Advanced Neurology PSD-95 in neurodevelopmental disorders

valproic acid during prenatal development show increased AMPARs, ultimately leading to an increase in glutamate
levels of PSD-95 in the hippocampus and cortex. These output (Figure 2D).
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studies affirm that disruptions in PSD-95 may be at the
core of synaptic structure and spine function issues. 3. Effect of pharmacotherapies for NDDs on
Intriguingly, various genes associated with autism, such PSD-95 levels
as protocadherin 10 (Pcdh10), FMRP, and myocyte enhancer 3.1. Effect of antipsychotics on PSD-95 levels
factor 2 (Mef2), have been linked to the breakdown of PSD- Several studies investigating the effects of antipsychotic and
95 and the elimination of synapses. This evidence supports NDD medications on the CNS of animal NDD models have
the notion that PSD-95-related deficiencies in synapse demonstrated several synaptic changes. Table 2 presents
elimination are standard features across various genetic selected examples of the impact of NDD pharmacotherapies
factors contributing to autism (Figure 2C). 51,56 on PSD-95 levels. SCZ treatment involves two types of

2.3. PSD-95 and ADHD drugs: typical and atypical antipsychotics. While the precise
mechanisms underlying their actions are not fully known,
ADHD is the most prevalent NDD, affecting approximately recent indications propose that atypical antipsychotics
5–7% of children/adolescents and around 2.5% of adults. may alter spine density, dendritic branching, and the
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In addition, ADHD is the most common neurobehavioral expression of synaptic protein markers such as synapsin,
comorbidity in children with epilepsy, affecting 4 – 65% SNAP-25, synaptophysin, and PSD-95 (Table 3). 30-32 In
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of children, a prevalence significantly higher than that contrast, the typical antipsychotic drug haloperidol either
observed in the general population. While research has decreases these elements or has no impact on them. 67,68
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implicated PSD-95 in various neuropsychiatric conditions Consequently, the effect of atypical antipsychotics on
and neurological disorders, including SCZ and ASD, its synaptic plasticity may underlie the greater clinical
direct role in ADHD remains less established. However, efficacy of atypical antipsychotics in contrast to typical
ADHD has been associated with disruptions in various agents. Atypical antipsychotic drugs might produce
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neurotransmitter systems and brain regions, suggesting positive effects by correcting deficiencies in the levels of
potential roles for PSD-95 in ADHD that has yet to be fully these proteins associated with synapses. Takaki et al.
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elucidated. For example, the monoaminergic hypothesis observed that dissociated cortical neurons from Sprague–
for ADHD, which postulates a pathogenic reduction Dawley rats treated with haloperidol (a butyrophenone-
of dopamine binding to its receptors, involves the type antipsychotic that is a high-affinity dopamine D2
modulation of several cognitive and executive processes receptor inhibitor) at concentrations of 1 and 10 mM
usually impaired in ADHD. PSD-95 modulates the for 2 days showed decreased PSD-95 protein levels and
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internalization of NMDAR, which may interact with spine numbers. However, given that therapeutic levels of
and thus influence the desensitization, trafficking, and haloperidol range from 5 to 20 nmol/L, the reduction in
signaling of dopamine receptors (Table 1). Studies PSD-95 and spine numbers observed by Takaki et al. may
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documenting altered concentrations of neurotransmitters be related to higher concentrations of haloperidol, which
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such as serotonergic, glutamatergic, and γ-aminobutyric 70
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acid (GABA) in ADHD suggest potential involvement has been reported to induce neurotoxicity and dystonia.
The quinolone atypical antipsychotic, aripiprazole, exhibit
of these systems, although they are not as widely greater selectivity in targeting the D2R/β-arrestin2
implicated as the dopaminergic system. It has also been scaffold signaling pathway, which can, in turn, influence
demonstrated that methylphenidate restores impaired GSK3β phosphorylation. Alterations in the Akt/GSK3
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glutamatergic transmission at the PFC and improves the pathway have been implicated in SCZ, and the interaction
ADHD phenotype in experimental models, with AMPAR between PSD-95 and Akt/GSK3 signaling may be involved
facilitating this process. Research on the signaling 72
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interplay between dopamine and glutamate indicates that in regulating neuronal progenitor proliferation and
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stimulation of the D2-class dopamine receptor results brain development. Reduced levels of PSD-95 would be
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in downstream inhibition of NMDARs. Similarly, the expected to decrease the Akt/GSK3 signaling, which is
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activation of D4 dopamine receptors reduces AMPAR- essential in regulating neurites and synaptic neuroplasticity.
mediated excitatory and GABAergic synaptic transmission Other antipsychotics with neuroprotective activity
in pyramidal neurons of the PFC, accompanied by a include olanzapine, quetiapine, clozapine, and ziprasidone.
decrease in AMPARs at the synapse induced by D4 Park et al. found that these antipsychotics increased the
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activation (as shown in Table 1). Consequently, in the expression of several proteins related to structure and
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ADHD brain characterized by a hypodopaminergic state, activity in hippocampal cultures deprived of the neuronal
one might anticipate heightened activity of NMDARs and cell culture supplement B27. Primary hippocampal cells
Volume 3 Issue 1 (2024) 6 https://doi.org/10.36922/an.2095