Synaptic basis of social dysfunction: a focus on postsynaptic proteins linking group‐I mGluRs with AMPARs and NMDARs

Abstract

Most of us engage in social interactions on a daily basis and the repertoire of social behaviors we acquire during development and later in life are incredibly varied. However, in many neurodevelopmental disorders, including autism spectrum disorders (ASDs), social behavior is severely compromised and indeed this represents a key diagnostic component for such conditions. From genetic association studies, it is increasingly apparent that genes identified as altered in individuals with ASDs often encode synaptic proteins. Moreover, these synaptic proteins typically serve to scaffold group-I metabotropic glutamate receptors (group-I mGluRs) and ionotropic glutamate receptors (iGluRs; AMPARs and NMDARs), or to enable group-I mGluR to iGluR crosstalk via protein synthesis. Here we aim to explore the possibility of a causal link between altered function of such synaptic proteins and impaired social behaviors that feature in neurodevelopmental disorders, such as ASDs. We review the known synaptic function and role in social behaviors of selected post-synaptic structural proteins (Shank, SAPAP and neuroligin) and regulators of protein synthesis (TSC1/2, FMRP and PTEN). While manipulations of proteins involved in group-I mGluR and iGluR scaffolding or crosstalk frequently lead to profound alterations in synaptic function and one or more components of social behavior, the neuronal circuits responsible for impairments in specific social behaviors are often poorly defined. We argue for an improved understanding of the neuronal circuits underlying specific social behaviors to aid the development of new ASD therapies.

Cognitive Enhancement

“…Mutations in genes encoding both AMPA and NMDA receptor subunits, which play critical roles in regulating synaptic transmission and plasticity, have been associated with ASD (Soto et al 2014). Additionally, genetic mutations found in some cases of ASD result in alterations in postsynaptic proteins necessary for receptor scaffolding and crosstalk between mGluRs and the iGluRs AMPA and NMDA (O'Connor et al 2014). Taken together, this genome-based research supports the hypothesis that abnormalities in genes involved in glutamate receptors and regulation of glutamate pathways may be directly involved in ASD pathology.…”

“…There are a variety of transgenic lines with disrupted glutamatergic function, via altered receptors or postsynaptic proteins linking mGluRs and iGluRs, that display disrupted social behavior analogous to the social impairment in ASD [see (Carlson 2012;O'Connor et al 2014) for review].…”

Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function

“…Increases [Huber, Gallagher, Warren, & Bear, ] and decreases [Bateup, Takasaki, Saulnier, Denefrio, & Sabatini, ] in LTD induced by application of Group 1 mGluR agonists have been identified in genetic models of autism. Furthermore, Group I mGluRs, as well as AMPARs and NMDARs, are being targeted for their therapeutic potential in ASD [Connor, Bariselli, & Bellone, ]. To determine whether Group I mGluR function is altered in Shank3 E13 mutants 100 μM DHPG was bath applied for 10 min and LTD was determined as the average fEPSP at 55–60 min following the start of DHPG washout, normalized to the average baseline fEPSP (Fig.…”

Ethanol-Associated Changes in Glutamate Reward Neurocircuitry: A Minireview of Clinical and Preclinical Genetic Findings

“…There are several scaffolding proteins within the PSD including membrane-associated guanylate kinases (MAGUKs), Shanks, and Homers. 59–61 Scaffolding proteins can be defined as molecules binding at least two other signaling proteins together. These scaffolding proteins are crucial for synaptic plasticity (e.g., learning and memory) by (1) acting as platforms where signaling molecules can assemble; (2) localizing signaling molecules at specific intracellular sites; (3) coordinating positive and negative feedback signals to modify intra- and extra-cellular signaling pathways; as well as (4) protecting these signaling pathways from inactivation, generally by preventing and/or disrupting phosphorylation.…”