Abstract
Disrupting the balance between excitatory and inhibitory neurotransmission in the developing brain has been causally linked with intellectual disability (ID) and autism spectrum disorders (ASD). Excitatory synapse strength is regulated in the central nervous system by controlling the number of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). De novo genetic mutations of the synaptic GTPase-activating protein (SynGAP) are associated with ID and ASD. SynGAP is enriched at excitatory synapses and genetic suppression of SynGAP increases excitatory synaptic strength. However, exactly how SynGAP acts to maintain synaptic AMPAR content is unclear. We show here that SynGAP limits excitatory synaptic strength, in part, by suppressing protein synthesis in cortical neurons. The data presented here from in vitro, rat and mouse cortical networks, demonstrate that regulation of translation by SynGAP involves ERK, mTOR, and the small GTP-binding protein Rheb. Furthermore, these data show that GluN2B-containing NMDARs and the cognitive kinase CaMKII act upstream of SynGAP and that this signaling cascade is required for proper translation-dependent homeostatic synaptic plasticity of excitatory synapses in developing cortical networks.
Highlights
Neurodevelopmental disorders such as non-syndromic forms of intellectual disability (ID) and autism spectrum disorders (ASD) involve disruptions in excitatory synaptic function
In order to control the strength of excitatory synaptic transmission and maintain proper E/I balance in developing brain circuits, levels of synaptic amino3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are tightly regulated
We report that synaptic GTPase-activating protein (SynGAP) acts as a critical regulator of AMPAR content at developing cortical synapses, in part, by limiting protein synthesis
Summary
Neurodevelopmental disorders such as non-syndromic forms of ID and ASD involve disruptions in excitatory synaptic function. ASDs affect 1% of the general population and are characterized by deficits in social interactions, communication, and manifestation of repetitive behaviors [1]. Dysregulated neurotransmission such as enhanced ratio of excitatory/inhibitory (E/I) synaptic balance has been proposed to underlie ASD [2]. Supporting this hypothesis, abnormal increases in synaptic strength have been demonstrated in mouse models of ASD [3,4,5,6]. Basal levels of AMPARs are tightly regulated allowing neurons to adjust synaptic strength rapidly in response to changes in network activity
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