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Advanced Neurology PSD-95 in neurodevelopmental disorders

Table 3. Effects of pharmacotherapies on PSD‑95 levels and mechanisms may provide insights into developing targeted
synaptic function therapies for individuals with SCZ and other related NDDs.
Pharmacotherapy Effect on PSD‑95 3.2. Effects of selective serotonin reuptake
Antipsychotics (i) Increase PSD-95 levels, spine numbers, and inhibitors (SSRIs) on PSD-95 levels
synaptic proteins. 43
(ii) May positively affect synaptic plasticity by The serotonin (5-HT) system plays a pivotal role in
correcting deficiencies in synaptic protein levels. 44 multiple aspects of neuronal development, including
(iii) Typical antipsychotics either decrease PSD-95 neurite outgrowth, the morphology of dendritic spines,
or have no significant impact. the organization of neural circuits, synaptic signaling, and
SSRI (i) SSRIs mitigate the decrease in PSD-95, enhance synaptic adaptability (as detailed in Table 3). Due to its
77
dendritic outgrowth, and increase BDNF levels central involvement in these processes, the 5-HT system
in hippocampal neurons. 77,98
(ii) Chronic administration of SSRIs can increase significantly impacts a range of conditions, including
PSD-95 levels, contributing to enhanced depression, anxiety, SCZ, and NDDs like ASD. 77,78 SSRIs,
synaptogenesis. 79 which enhance serotonin activity by inhibiting its reuptake,
(iii) Increase the presence of postsynaptic 5-HT2A are commonly used as antidepressant medications.
receptors. 121 In addition to their antidepressant properties, several
α2-Ars (i) α2-Ars increase spine density, stimulate potential neuroprotective effects of SSRIs have been
PSD-95 expression, and impact synaptic documented. 79,80
function and plasticity. 74
(ii) α2-Ars shows promise in enhancing working Beyond their impact on presynaptic receptors, continuous
memory and addressing PFC-related issues in SSRI treatment may also increase the presence of postsynaptic
children and adolescents. 106 5-HT2A receptors. Serotonergic psychedelics induce
Other therapies (i) Memantine: It can restore normal synaptic translocation of 5-HT2A receptors from the cell surface
plasticity and extend the duration of into the cytoplasm. 81,82 Interestingly, atypical antipsychotics,
NMDAR-dependent LTP. 108 Limited
exploration in psychiatric disorders like SCZ as acting as 5-HT2A receptor antagonists, also trigger this
83
adjunctive therapy. internalization. Notably, PSD-95-mediated anchoring of
(iii) Allopurinol: Increases PSD-95 and BDNF 5-HT2A receptors to the cell membrane appears crucial for
expression. 112 the immediate effects of both psychedelics and atypical
(iii) Ketamine: PSD-95/NMDAR2A levels increase in 84 Dec
various brain regions (cerebellum, hippocampus, antipsychotics. reased levels of 5-HT2A receptors
striatum). Temporarily enhances synaptic have been observed following prolonged SSRI use, 85-87 and
119
connections through glutamate bursts and disrupting the genetic signaling of 5-HT2A was found
NMDAR activity modulation. to interfere with the antidepressant effects of SSRIs.
88
Abbreviations: α2-Ars: Alpha-2 adrenergic agonists; For instance, SSRIs such as fluoxetine, citalopram, and
BDNF: Brain-derived neurotrophic factor; LTP: Lon-term potentiation; escitalopram have demonstrated the ability to enhance
NMDAR: N-methyl-d-aspartic acid receptors; PFC: Prefrontal cortex; clinical recovery and reduce disability in patients who
PSD-95: Postsynaptic density-95; SCZ: schizophrenia; SSRIs: Selective 89
serotonin reuptake inhibitors have experienced brain ischemia. Moreover, Aguiar
90
et al. revealed that the administration of 20 mg/kg of
10 µM of aripiprazole used for 2 days in dissociated cortical escitalopram for 28 days reduced anxiety-like behavior
neurons from Sprague–Dawley rats increased PSD-95 and and mitigated the decrease in PSD-95 protein levels in
69
spine numbers. Another antipsychotic that increases the PFC of mice subjected to bilateral carotid artery
PSD-95 in both cortex and striatum is asenapine, inducing occlusion (BCCAO). They concluded that PSD-95
a pronounced increase in PSD-95 mRNA levels (p=0.002) plays a role in modulating the strength of excitatory
91
more significantly than haloperidol in male Sprague– neurotransmission, and restoring PSD-95 may determine
Dawley rats. In addition, chronic administration of the the extent of functional recovery after an ischemic
75
event. When primary hippocampal cells obtained from
90
antipsychotic ziprasidone (4 mg/kg) evaluated at 90 min Sprague–Dawley rats were cultured without B27 in the
increased PSD-95 levels in the anterior cingulate cortex medium, they exhibited reduced cell death when treated
(ACC). 76
with a range of SSRIs, including escitalopram, fluoxetine,
The mechanisms proposed for the therapeutic benefit paroxetine, sertraline, imipramine, tranylcypromine, and
derived from these second-generation antipsychotics are tianeptine. 92,93 In addition, the SSRIs effectively prevented
largely theoretical; further basic and clinical studies are the decline in PSD-95, BDNF, and synaptophysin levels
needed to elucidate the exact cause behind the observed induced by B27 deprivation. Furthermore, in normal
clinical benefits. Ultimately, understanding the molecular conditions, fluoxetine, paroxetine, and sertraline notably

Volume 3 Issue 1 (2024) 9 https://doi.org/10.36922/an.2095