- Awarded: 2020
- Award Type: Pilot
- Award #: 724187
The cerebral cortex contains diverse types of excitatory projection neurons and inhibitory interneurons that form specific circuits to support healthy brain function. To assemble these circuits during development, neuronal subtypes must be properly generated during embryonic periods and subsequently choose their correct synaptic partners. Mutations in chromatin-modifying protein complexes can disrupt prenatal neuronal differentiation and proliferation, resulting in abnormal postnatal cortical development and autism spectrum disorders (ASDs). However, the specific changes to synaptic connectivity and physiology that produce these aberrant circuit configurations remain poorly understood.
Jason Wester and his colleagues at Ohio State University propose to study a mouse model of Arid1b haploinsufficiency, which is known to result in ASD and moderate to severe intellectual disability in humans. Arid1b encodes a chromatin remodeling complex subunit necessary for the proper development of both excitatory projection neurons and inhibitory interneurons. Wester’s team plans to conditionally knockout one copy of Arid1b from either projection neurons or interneurons during embryonic development. They will subsequently use paired whole-cell recordings to study the formation of synaptic connections during postnatal development between neighboring neurons that are either heterozygous for Arid1b or wildtype.
Their studies will span from early postnatal development to adulthood to learn how and when the trajectory of circuit formation is disrupted. During the first postnatal week, they will investigate early patterns of synaptic connectivity and the emergence of intrinsic network activity generated by the immature cortex. In mature mice, they will test circuit motifs observed among different classes of excitatory projection neurons and distinct subtypes of inhibitory interneurons. Their work will provide important insight into the relative contributions of these neurons to the development of microcircuit-level ASD pathology.