Cellular mechanisms of GABAergic inhibition in neocortical dendrites

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DESCRIPTION (provided by applicant): Cortical GABAergic interneurons (INs) play critical roles in controlling normal patterns of brain activity and are implicated in the pathophysiology of neuropsychiatric disease. While many INs target pyramidal neuron (PN) somata, where they regulate the magnitude and timing of spike output, the majority of GABAergic synapses are formed onto PN dendrites, where their role in cellular function is less well understood. Dendrite-targeting interneurons that express the peptide somatostatin (SOM-INs) are hypothesized to provide negative feedback to distal PN dendrites that scales with local network activity. However, technical limitations to selectively controlling the output of these neurons while simultaneously measuring dendritic activity with high spatial resolution have prevented a clear elaboration of SOM-IN function. Our long-term goal is to understand how distinct pools of GABAergic INs contribute to cellular and circuit regulation in the prefrontal cortex (PFC), a brain region associated with higher cognitive processes that may be disrupted in illnesses such as schizophrenia. In this proposal, our primary objective is to identify how SOM-INs regulate calcium (Ca) signaling in the dendrites of PFC PNs. We also focus on understanding how dendritic inhibition is shaped by the intrinsic voltage-gated properties of PN dendrites and the neuromodulator dopamine. Our central hypothesis is that GABAergic inhibition is both heterogeneous and compartmentalized in PN dendrites. We expect that this compartmentalization is dependent on many factors, including the spatiotemporal pattern of inhibitory synaptic activation and the electrical properties of dendritic structures such as spines Guided by strong preliminary data, we will examine this central hypothesis in three specific aims: 1) Determine the role of GABAergic inhibition in shaping dendritic Ca signaling. 2) Identify the voltage-gated dendritic conductances that contribute to inhibitory synaptic integration. 3) Determine the actions of dopamine on dendritic inhibition and Ca signaling. The data generated by these experiments will generate new insights into the contribution of GABAergic transmission to both neuronal cell biology and the function of cortical circuits. We expect our results will als highlight new avenues into the investigation of the pathophysiology underlying neuropsychiatric disorders resulting from perturbation of both GABAergic and dopaminergic signaling. PUBLIC HEALTH RELEVANCE: Inhibitory GABAergic neurons provide important control over the activity of neurons in the neocortex. This proposal will determine the role of GABAergic synapses in regulating calcium, a key biochemical signaling molecule, within the dendrites of cortical neurons. Results from these studies will help identify novel cellular mechanisms that may contribute to the pathophysiology of neuropsychiatric disorders and suggest new avenues for therapeutic intervention.