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Advanced Neurology PSD-95 in neurodevelopmental disorders

increased BDNF levels. Importantly, all antidepressant memory, promote the growth of dendritic spines in
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medications significantly enhanced the overall outgrowth the PFC, and reduce inflammation. Consequently, it may
of dendrites in hippocampal cells, even in the absence of have potential benefits across a wide range of mental
B27. Particularly, tianeptine, a selective serotonin reuptake disorders. The drug is already in widespread (off-
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enhancer, promoted dendritic outgrowth via PI3K label) use to address trauma-related issues in children
signalling. The PI3K/Akt signaling plays a central role in and adolescents, mainly when there are signs of PFC
determining dendritic morphogenesis. 94 dysfunction, such as difficulties in emotion regulation
The impact of fluoxetine on PSD-95 has also been widely (e.g., impulsive aggression) and attention problems, which
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studied. Chronic fluoxetine administration in mice has are common and challenging. Daily administration
been shown to mitigate the reduction in hippocampal PSD- of guanfacine at a dose of 0.1 mg/kg subcutaneously
95 levels induced by depression, consequently increasing before exposure to stress has been shown to safeguard
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PSD-95 levels in the hippocampus. Similarly, when mice working memory performance and spine density in male
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were administered fluoxetine at a dose of 20 mg/kg and rats. The study observed a notable connection between
ferulic acid at a dose of 40 mg/kg separately, a significant cognitive capabilities and spine density on dendritic trees’
increase in PSD-95 levels was observed in both the PFC distant apical and basal segments. This finding supports
(P < 0.05 for both) and the hippocampus (P < 0.05 for a meaningful association between the structural integrity
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fluoxetine and P < 0.01 for ferulic acid). However, when of dendrites in the PFC and cognitive function. While
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ferulic acid was administered at a lower dose of 20 mg/kg, the direct interaction between α2-AR and PSD-95 has not
it led to a significant increase in PSD-95 levels only in the been extensively analyzed, certain studies have investigated
hippocampus (P < 0.05). Li et al. demonstrated that oral the effects of α2-AR-linked medications on synaptic
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administration of citalopram (10 mg/kg) in an endogenous function and plasticity. For instance, Ren et al. observed
depression rat model increased dendritic spine density that activation of α2-ARs by guanfacine increased PSD-
and significantly increased PSD-95 levels (P < 0.0001) in 95 expression and significantly induced stubby (from
both the hippocampus and PFC. Given the role of PSD- 10% to 14%) and mushroom spines (from 43% to 59%),
95 in spine formation, these findings suggest that various along with enlargement of spine head size in cultured PFC
antidepressant drugs may promote new synapse formation neurons. Since PSD-95 is an essential player in synaptic
in hippocampal neurons. Further study of the effects of function and plasticity, it is possible that the modulation of
different classes of antidepressant medications on PSD- synaptic activity by α2-ARs could indirectly impact PSD-
95 and associated proteins may elucidate the common 95 and related signaling pathways. However, more research
pathways that contribute to enhanced synaptogenesis. is needed to fully understand the interactions between
α2-AR and PSD-95 and their implications for neurological
3.3. Effects of alpha-2 adrenergic agonists on PSD- and neuropsychiatric conditions.
95 levels
Alpha-2 adrenergic agonists (α2-ARs) are a class of 3.4. Effects of alternative treatments for NDDs on
medications that stimulate alpha-2 adrenergic receptors PSD-95 levels
in the brain and peripheral nervous system. These As outlined above, a variety of medications are
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medications can have various effects, including reducing commonly used to manage specific NDD symptoms or
sympathetic nervous system activity, leading to relaxation co-occurring conditions. In addition, there are alternative
and decreased heart rate (Table 3). In addition, α2-ARs pharmacotherapies that may be considered for NDDs:
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modify transmitter biosynthesis or depolarization-evoked
transmitter release on presynaptic neurons. 101 3.4.1. Memantine
Drugs such as clonidine and guanfacine stimulate Memantine, a partial uncompetitive trapping blocker of
alpha-2 adrenergic receptors in the brain and spinal NMDA channel receptors, is presently employed to manage
cord. 99,101 The stimulation of α2-ARs significantly moderate-to-severe AD. It is well tolerated and does not
contributes to the increase in spine density, facilitating produce psychotomimetic effects, meaning that it does
network connectivity. Guanfacine, a selective α2-AR not induce psychosis. In addition, memantine can restore
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2+
agonist, differs from other drugs such as clonidine, normal synaptic plasticity, reduce Mg concentration, and
which targets both α2-ARs and imidazoline receptors. extend the duration of NMDAR-dependent post-synaptic
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Studies have reported that guanfacine can produce LTP, a critical process for forming neuronal memories.
dose-dependent antinociception in mouse models of Beyond its conventional use, memantine has been
formalin-induced inflammatory colonic pain. Moreover, explored in a limited number of case reports for off-label
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guanfacine has been demonstrated to enhance working applications, notably in psychiatric disorders, primarily
Volume 3 Issue 1 (2024) 10 https://doi.org/10.36922/an.2095