Dissecting inhibitory microcircuits during learning in a mouse model of Dravet syndrome

  • Awarded: 2016
  • Award Type: Explorer
  • Award #: 480176

Autism spectrum disorders (ASDs) encompass a number of disorders that are typified by communication deficits, reduced behavioral flexibility, poor socialization, learning disabilities and a tendency toward repetitive behaviors. While the pathophysiology underlying ASDs remains largely unknown, the recent identification of gene mutations associated with ASDs has significantly advanced our understanding of these disorders. Many gene mutations found in ASDs have been shown to affect the formation, functional efficacy and plasticity of both excitatory and inhibitory synapses. Hence, a hypothesis of an imbalanced neuronal excitation and inhibition has been put forward as an underlying cause of ASDs.

Simon Chen and his collaborators have previously demonstrated that motor learning causes a differential remodeling of inhibition along pyramidal neurons in the motor cortex that is mediated by two distinct populations of inhibitory interneurons: somatostatin- and parvalbumin-expressing cells1. Interestingly, studies have also reported that individuals with ASD exhibit deficits in basic motor control (reach-to-grasp movements) and motor learning. Hence, it is intriguing to examine whether the motor deficits observed in those with ASDs are also caused by perturbed inhibitory networks in the motor cortex. Moreover, it is of high importance to dissect the inhibitory microcircuits within the motor cortex and pinpoint how inhibitory neuron subtypes may contribute the network dysfunction in ASDs.

To address these questions, Chen and his lab plan to utilize a mouse model of Dravet syndrome, a developmental epileptic syndrome that shares many symptoms with ASDs. Dravet syndrome is caused by heterozygous loss-of-function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel subunit Nav1.1, in inhibitory neurons, providing an elegant animal model for studying perturbed inhibitory networks in ASDs. The researchers propose a series of experiments employing in vivo two-photon imaging, combined with a novel forelimb lever-press task for head-fixed mice to elucidate microcircuit functions and perturbation in SCN1A +/- mice. Furthermore, they will directly visualize activity and molecular events with cellular and subcellular resolution in the intact brain of awake and behaving mice to link pathophysiological changes in structural and functional plasticity with ASD-related behavioral deficits in motor control and learning. The findings from these studies are expected to have a significant impact on the development of therapeutic strategies for counteracting neural circuit dysfunctions associated with ASDs.



1.Chen S.X. et al. Nat. Neurosci. 18, 1109–1115 (2015) PubMed
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