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Review
. 2018 Mar 2:82:187-194.
doi: 10.1016/j.pnpbp.2017.11.016. Epub 2017 Nov 21.

PSD95: A synaptic protein implicated in schizophrenia or autism?

Austin A Coley  1 , Wen-Jun Gao  2
Affiliations
Review

PSD95: A synaptic protein implicated in schizophrenia or autism?

Austin A Coley et al. Prog Neuropsychopharmacol Biol Psychiatry. .

Abstract

The molecular components of the postsynaptic density (PSD) in excitatory synapses of the brain are currently being investigated as one of the major etiologies of neurodevelopmental disorders such as schizophrenia (SCZ) and autism. Postsynaptic density protein-95 (PSD-95) is a major regulator of synaptic maturation by interacting, stabilizing and trafficking N-methyl-d-aspartic acid receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid receptors (AMPARs) to the postsynaptic membrane. Recently, there has been overwhelming evidence that associates PSD-95 disruption with cognitive and learning deficits observed in SCZ and autism. For instance, recent genomic and sequencing studies of psychiatric patients highlight the aberrations at the PSD of glutamatergic synapses that include PSD-95 dysfunction. In animal studies, PSD-95 deficiency shows alterations in NMDA and AMPA-receptor composition and function in specific brain regions that may contribute to phenotypes observed in neuropsychiatric pathologies. In this review, we describe the role of PSD-95 as an essential scaffolding protein during synaptogenesis and neurodevelopment. More specifically, we discuss its interactions with NMDA receptor subunits that potentially affect glutamate transmission, and the formation of silent synapses during critical time points of neurodevelopment. Furthermore, we describe how PSD-95 may alter dendritic spine morphologies, thus regulating synaptic function that influences behavioral phenotypes in SCZ versus autism. Understanding the role of PSD-95 in the neuropathologies of SCZ and autism will give an insight of the cellular and molecular attributes in the disorders, thus providing treatment options in patients affected.

Keywords: AMPAR; Autism; Glutamate; NMDAR; Neurodevelopment; PSD-95; Schizophrenia.

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Conflict of interest statement

Disclosure of Conflicts of Interest

The authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1
Figure 1
PSD-95 interactions in the PSD. An illustration describing the molecular organization of the postsynaptic density (PSD) located in the dendritic spine of glutamatergic synapses. Postsynaptic density-95 (PSD-95) contains direct and indirect interactions with many macromolecules at the PSD. PDZ1 domains of PSD-95 bind directly to N-methyl-D-aspartic acid receptors (NMDARs), more specifically, NR2-containing NMDA-receptors. PSD-95 also interacts with ErbB4, neuroligin, and nNos. PSD-95 has indirect interactions with α-amino-3-hydroxy-5-methyl-4- isox-azoleproprionic acid receptors (AMPARs) via stargazin. Other indirect interactions include group 1/5 mGluRs via GKAP, shank, and homer; and actin polymers via GKAP and cortactin. nNos, Neuronal nitric oxide synthase; GKAP, guanylate kinase-associated protein; mGluR, metabotropic glutamate receptors.
Figure 2
Figure 2
Dendritic spine changes in schizophrenia. (A) Graph showing dendritic spine development in patients with schizophrenia (yellow) versus normal brains (black). (B) Hypothetical models for the decrease in number of dendritic spines in SCZ patients. PSD-95 mutations disrupt ErbB4-neuregulin signaling causing AMPAR’s to destabilize from the postsynaptic membrane and a loss of NMDAR’s. However, enhanced neuregulin-Erb4 signaling leads to NMDAR hypofunction and loss of spines. A disrupted or deficient amount of PSD-95 results in a loss of NMDAR’s (NR2A-containing) and AMPAR receptors present at the membrane.
Figure 3
Figure 3
Dendritic spine changes in autism. (A) Graph showing dendritic spine development in autism patients (orange) versus normal brains (black). (B) Hypothetical models for the increase in number of dendritic spines within autism patients. The absence of FMRP causes a reduction in PSD-95 degradation and subsequent increase in AMPAR recruitment to the postsynaptic membrane. FMPR dephosphorylation causes an increase in PSD-95 translation via group 1 mGluR activation, thus increasing AMPAR recruitment to the postsynaptic membrane.
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