Synaptic basis of social dysfunction: a focus on postsynaptic proteins linking group-I mGluRs with AMPARs and NMDARs.
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.
Department of Basic Neurosciences, Medical Faculty, University of Geneva, 1 Rue Michel Servet, CH-1211, Geneva, Switzerland.
Eoin C
EC
O'Connor
Sebastiano
S
Bariselli
Camilla
C
Bellone
D000818:Animals; D002659:Child Development Disorders, Pervasive / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000502:physiology
D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate
AMPAR; Autism; NMDAR; development; mGluR