SAPAP Scaffold Proteins: From Synaptic Function to Neuropsychiatric Disorders

Abstract

Excitatory (glutamatergic) synaptic transmission underlies many aspects of brain activity and the genesis of normal human behavior. The postsynaptic scaffolding proteins SAP90/PSD-95-associated proteins (SAPAPs), which are abundant components of the postsynaptic density (PSD) at excitatory synapses, play critical roles in synaptic structure, formation, development, plasticity, and signaling. The convergence of human genetic data with recent in vitro and in vivo animal model data indicates that mutations in the genes encoding SAPAP1–4 are associated with neurological and psychiatric disorders, and that dysfunction of SAPAP scaffolding proteins may contribute to the pathogenesis of various neuropsychiatric disorders, such as schizophrenia, autism spectrum disorders, obsessive compulsive disorders, Alzheimer’s disease, and bipolar disorder. Here, we review recent major genetic, epigenetic, molecular, behavioral, electrophysiological, and circuitry studies that have advanced our knowledge by clarifying the roles of SAPAP proteins at the synapses, providing new insights into the mechanistic links to neurodevelopmental and neuropsychiatric disorders.

Mapping proteomic composition of excitatory postsynaptic sites in the cerebellar cortex

“…We chose Shank1-3 for assessment because of their importance in neurodevelopmental disorders as discussed in the introduction. We assessed another excitatory postsynaptic scaffold protein, SAPAP1 (also known as DLGAP1, DAP1 and GKAP), which functions to link Shank proteins to PSD-95 ( Naisbitt et al, 1999 ; Bai et al, 2022 ). Mutations in the human gene encoding SAPAP1 are also associated with neuropsychiatric disorders, including a de novo CNV in schizophrenia ( Kirov et al, 2012 ; Bai et al, 2022 ).…”

Advancements in the study of synaptic plasticity and mitochondrial autophagy relationship

“…(Rasmussen et al., 2017) Members of the DLGAP (SAPAP) family mainly cooperate with each other at excitatory synapses and interact with proteins like PSD‐95, SAP97, and the Shank family through structural domains. Together, they participate in regulating synaptic formation, structural stability, signal transduction, and synaptic plasticity (Bai et al., 2022).…”

“…interact with proteins like PSD-95, SAP97, and the Shank family through structural domains. Together, they participate in regulating synaptic formation, structural stability, signal transduction, and synaptic plasticity(Bai et al, 2022).CaMKI is primarily expressed in the nervous system and is involved in regulating synaptic plasticity. The mammalian CaMKI family consists of four members encoded by four different genes: CaMK1 (CaMKIα), PNCK (CaMKIβ/Pnck), CAMK1G (CaMKIγ/CLICK3), and CAMK1D (CaMKIδ/CKLiK) (Takemoto-Kimura et al, 2017).…”

Synapse Dysfunctions in Multiple Sclerosis

“…The neurotransmitter receptors are enriched in the postsynaptic density (PSD) that is located directly opposite to the active zone. In the PSD, neurotransmitter receptors are immobilized by a dense protein network of scaffold proteins [ 120 , 121 ]. These scaffold proteins include MAGUK family proteins, e.g., PSD-95, SAP-97, SAP-102, in excitatory synapses.…”

“…Inhibitory synapses contain scaffold proteins such as gephyrin and collybistin [ 122 ]. PSD-95 of excitatory synapses is a particularly relevant PSD scaffold protein of excitatory synapses because it links AMPA- and NMDA-type glutamate receptors to each other [ 120 , 121 ]. These glutamate receptors are important for synaptic plasticity and for excitotoxic synapse damage (see below).…”