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Advanced Neurology PSD-95 in neurodevelopmental disorders

1. Introduction

Neurodevelopmental disorders (NDDs) are early-onset
neurological disorders characterized by impaired brain
development, resulting in dysregulation of normal cognitive
and motor development, leading to decreased cognition,
communication, adaptive behavior, and psychomotor
skills. NDDs encompass a range of conditions, including
autism spectrum disorder (ASD), schizophrenia (SCZ),
attention deficit hyperactivity disorder (ADHD), and
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epilepsy. Collectively, these disorders impose significant
health and societal costs, affecting more than 3% of
children worldwide. Nonetheless, diagnosing NDDs can
2
be complicated due to overlapping signs and symptoms
that are not unique to a single NDD. In addition, there is
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frequently a substantial delay, with disease onset preceding
diagnosis by significant periods.
Despite this inherent heterogeneity, a common feature
of many NDDs is the alteration of the molecular pathways
underlying synaptic plasticity. Synaptic plasticity refers
4,5
to the modulation of the strength of inter-neuronal
connections, an essential neurophysiological process
associated with brain network formation, typical central
nervous system (CNS) function, and the CNS response to
injury.6 Alterations in synaptic plasticity can manifest in
various forms, including anti-homeostatic (i.e., Hebbian) Figure 1. The structural organization of PSD-95 protein domains, their
arrangement into supramodules, and their interactions with selected
and homeostatic (i.e., synaptic scaling) mechanisms. proteins. Starting from the N-terminal (Nt) to the C-terminal (Ct), PSD-
6,7
Long-term potentiation (LTP) represents an essential 95 comprises three PDZ domains (PDZ1 to 3), an SH3 domain, and a
manifestation of synaptic plasticity, characterized by the guanylate kinase-like (GK) domain.
activity-driven strengthening of synapses, which involves Abbreviations: GK: Guanylate kinase; GKAP: Guanylate kinase-
dendritic spine remodeling, increased spine volume, associated protein; MAP1a: Microtubule-associated protein 1a; nNOS:
Neuronal nitric oxide synthase; PDZ: PSD-95/disks large/zona occludens;
stability, and clustering, ultimately leading to a long-lasting PSD-95: Postsynaptic density-95; SH3: Src homology 3.
increase in neuronal transmission. The induction of LTP
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is mainly dependent on the activation of n-methyl-d- carboxy-terminal tails of NMDAR subunits NR2A
aspartate (NMDA) receptor (NMDAR). The functional and NR2B through its PDZ domains, as well as with
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characteristics of this receptor inform several fundamental α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
properties of this type of synaptic plasticity. A family (AMPA) receptors (AMPARs) accessory proteins such
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of synaptic scaffolding proteins known as membrane- as stargazin/TARPs. Its early localization at synapses
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associated guanylate kinases (MAGUKs) serves as central compared to other PSD proteins suggests its potential role
modulators of both constitutive and activity-dependent in shaping the PSD’s structure, thereby influencing synapse
trafficking of NMDAR. 11 shape, strength, and differentiation. In addition, PSD-95
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The PSD family of synaptic MAGUKs, consisting is a crucial part of the complex network of proteins in the
of postsynaptic density-95 kDa (PSD-95), PSD-93, PSD, including ion channels, receptors, adhesion proteins,
and synapse-associated protein 102 (SAP-102), is scaffolding proteins, and signaling molecules, all of which
notably abundant at excitatory synapses. Within collectively impact glutamate transmission. It directly
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+
the PSD-MAGUKs family, PSD-95 has received the interacts with K channels, neuroligin, and neuronal nitric
most comprehensive attention and study concerning oxide synthase (nNOS) while indirectly interacting with
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synaptic plasticity. Structurally, PSD-95 comprises three mGluR1/5 through guanylate kinase-associated protein.
PSD-95/disks large/zona occluden (PDZ) domains at its Over 95% of PSD-95 localizes to excitatory synapses,
N-terminus (PSD-95, DLG, and zonula occludens-1), an where it plays a crucial role in anchoring AMPARs
SH3 domain, and an inactive guanylate cyclase domain and the NMDAR complex within the PSD. PSD-95
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(GK) (Figure 1). PSD-95 directly interacts with the involvement in synaptic plasticity within glutamatergic
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Volume 3 Issue 1 (2024) 2 https://doi.org/10.36922/an.2095