Arid1b haploinsufficiency in excitatory neurons alters neocortical circuits but not social behavior or seizure phenotypes.

Abstract

Arid1b is a high confidence risk gene for autism spectrum disorder that encodes a subunit of a chromatin remodeling complex initially expressed in neuronal progenitors. Haploinsufficiency causes a broad range of social, behavioral, and intellectual disability phenotypes, including Coffin-Siris syndrome. Recent work suggests pathology is due to deficits in proliferation, survival, and synaptic development of cortical neurons. Here, we used transgenic mice to investigate how Arid1b dysfunction in cortical excitatory neurons impacts their intrinsic membrane properties, synaptic connectivity and physiology of local cortical circuits using paired whole-cell recordings, social behavior, and seizure susceptibility. We found that loss of both copies of Arid1b altered the proportions of different excitatory neuron cell-types in the superficial cortical layers; however, their intrinsic membrane properties were mostly unchanged. In mice with conditional Arid1b haploinsufficiency in excitatory neurons, we found an increase in the rate of synaptic connectivity between excitatory neurons and reduced strength of excitatory synapses to parvalbumin (PV)-expressing inhibitory interneurons. In the deep cortical layers, we found hyperpolarization of action potential threshold. Collectively, these data suggest an increase in the ratio of excitation to inhibition. However, we also found enhanced inhibition from PV interneurons to excitatory neurons that may rebalance this ratio. Indeed, Arid1b haploinsufficiency in excitatory neurons was insufficient to cause social deficits and seizure phenotypes observed in a preclinical germline haploinsufficient mouse model. Our data suggest that while excitatory neurons likely contribute to autistic phenotypes, pathology in these cells is not the primary cause.