SYNGAP1 Links the Maturation Rate of Excitatory Synapses to the Duration of Critical-Period Synaptic Plasticity

Abstract

Critical periods of developmental plasticity contribute to the refinement of neural connections that broadly shape brain development. These windows of plasticity are thought to be important for the maturation of perception, language, and cognition. Synaptic properties in cortical regions that underlie critical periods influence the onset and duration of windows, although it remains unclear how mechanisms that shape synapse development alter critical-period properties. In this study, we demonstrate that inactivation of a single copy of syngap1, which causes a surprisingly common form of sporadic, non-syndromic intellectual disability with autism in humans, induced widespread early functional maturation of excitatory connections in the mouse neocortex. This accelerated functional maturation was observed across distinct areas and layers of neocortex and directly influenced the duration of a critical-period synaptic plasticity associated with experience-dependent refinement of cortical maps. These studies support the idea that genetic control over synapse maturation influences the duration of critical-period plasticity windows. These data also suggest that critical-period duration links synapse maturation rates to the development of intellectual ability.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…In mice, SynGAP1 accelerates the maturation of dendritic spines leading to disruptions in synaptic transmission and cognitive function [307][308][309][310] . Several de novo mutations of SYNGAP1 have also been associated with ASD 43,64,306,[311][312][313][314][315] .…”

MicroRNA-137 Controls AMPA-Receptor-Mediated Transmission and mGluR-Dependent LTD

“…Recently, in animal models of ASD, such indiscriminative unsilencing of synapses has been shown to lead to distorted neuronal network formation. For example, haplo-insufficiency of Syngap1 in mice leads to premature maturation of hippocampal and cortical synapses, resulting in a shortening of the critical period for plasticity (Clement et al, 2012(Clement et al, , 2013.…”

Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders

“…Moreover, glutamatergic synaptic transmission and the AMPA/NMDA ratio were transiently enhanced in Syngap1 +/-mice only during early developmental stages despite the persistence of behavioral deficits throughout adulthood, when the level of glutamatergic transmission becomes comparable to that of wild-type littermates (Clement et al, 2013). Consistent with this finding, reducing SYNGAP1 expression in adulthood has minimal impact on the AMPA/NMDA ratio, as well as cognition and behavior, demonstrating that SYNGAP1 plays critical roles in neural development (Clement et al, 2013). Not surprisingly, reducing SYNGAP1 expression in GABAergic inhibitory neurons did not impair cognition or neurotransmission (Ozkan, Creson, Kramar, Rojas, Seese, Babyan et al, 2014).…”

“…Interestingly, Syngap1 haploinsufficiency accelerates the maturation of glutamatergic synapses in the early postnatal period (Clement et al, 2012;Clement, Ozkan, Aceti, Miller, & Rumbaugh, 2013). Moreover, glutamatergic synaptic transmission and the AMPA/NMDA ratio were transiently enhanced in Syngap1 +/-mice only during early developmental stages despite the persistence of behavioral deficits throughout adulthood, when the level of glutamatergic transmission becomes comparable to that of wild-type littermates (Clement et al, 2013).…”