Cortical inhibition has critical roles in not only stabilization of neural circuit activity but also delicate control of frequency and timing of neuronal spiking, which underlie proper cortical processing. Therefore, a malfunction of inhibitory circuits could lead to severe brain disorders such as epilepsy, autism and schizophrenia. In the cortex, inhibition is mediated through local GABAergic interneurons, which comprise approximately 20% of the cortical neuronal population. Although numerically minor, GABAergic neurons display a large degree of heterogeneity regarding morphology, physiology, and connectivity. This striking feature has been thought to confer a rich repertory of inhibitory controls on neural circuitry and enable various types of neuronal computations. Thus, studying development, connectivity and function in each subtype of GABA neurons should tell us a blueprint of brain circuits, a principle of local circuit formation and ultimately hints for how the brain works. We have generated and characterized over 20 Cre and inducible CreER knockin lines, which reliably target major subtypes of GABAergic interneurons. Taking full advantage of this genetic resource we will ask following questions:
An excitatory pyramidal neuron receives many inhibitory inputs from different classes of GABAergic interneurons, forming a basic circuit motif. An interesting feature in connectivity of GABA neurons is that their distinct subtypes innervate different compartments (e.g. dendrite, cell soma and axon initial segment) of a pyramidal neuron, which must have different inhibitory impacts. However, our knowledge about subtype-specific connectivity of GABA neurons has been quite limited. First, we will develop a new method to visualize inputs only from a specific subtype of GABA neurons and systematically unravel subtype-specific connectivity. Second, we will examine how subtype-specific connectivity is established during development.
Chandelier cell biology
We will ask more specific questions such as specification, axonal and synaptic development and physiological function of a subtype of GABA neurons, using chandelier cells as a model case, which exclusively innervate pyramidal cell axon initial segments, the sites of action potential initiation. To answer these questions we will use state of the art imaging techniques and genetic approaches.