Neurodevelopmental Disorder Risk Gene Regulation of Intrinsic Membrane Excitability: A Rheostat that Tunes Dendritic Morphogenesis to Regulate Circuit Assembly During Development

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Project Summary The goal of this project is to understand how gene expression during development shapes the delicate and massively parallel cell biological processes that promote wiring of functional networks within the cerebral cortex. This is an important area of basic research because neural dynamics within cortical networks are the direct correlates of thought and behavior. These cognitive processes emerge as neural circuits form through expression of genes over the course of development. Moreover, cognitive impairment, which defines neurodevelopmental disorders (NDDs), is thought to arise, at least in part, from impaired neural circuit connectivity within the developing cortex. A revelation over the past decade is that NDDs can be caused by de novo genetic loss-of-function SNVs within a single gene. Thus, in-depth study of natural functions of these genes can reveal the neurobiological principles underlying the typically developing cortex and as well as principles that contribute to abnormal cortical development associated with NDDs. In this project, we will explore the hypothesis that expression of NDD-associated genes in the typically developing cortex promotes the assembly of cortical circuits through cell-autonomous regulation of intrinsic membrane excitability. This hypothesis is significant because it is known that neural activity shapes the assembly of developing cortical circuits. However, it remains unknown how genes function at the cellular level to promote activity-dependent in vivo development of cortical circuit motifs known to promote cognitive function and behavioral adaptations. Aim 1 will explore the causal relationships between genetic control of intrinsic membrane excitability (IME), activity- dependent dendritic morphogenesis, and developmental assembly of cortical circuits. Aim 2 will explore causal links between genetic control of IME, neuronal ensemble structure/function, and behavioral adaptations. We will do this by regulating genetic control of IME in developing cortical neurons and then observing the effect of this on cortical ensembles and behavioral adaptions. This research design is important because the brain functions across multiple temporal and spatial scales – indeed, this project attempts to link gene function across the major levels of brain function – gene>neuron>synapse>circuit>ensemble>behavior. The overall impact of this proposed research is that it has the potential to reveal how gene expression shapes the activity- dependent assembly of neural circuits that promote cognitive functions required for behavioral adaptations. Because we focus on natural functions of an NDD gene, these basic insights are also directly relatable to the etiology of cortical wiring impairments associated with childhood brain disorders.