Cellular mechanisms of GABAergic inhibition in neocortical dendrites

SUMMARY The development, function, and plasticity of GABAergic circuits in the neocortex are critical processes for establishing and maintaining normal patterns of brain activity. Moreover, the dysregulation of GABA signaling is implicated in a number of neuropsychiatric disorders, including schizophrenia and autism. The majority of studies on GABAergic transmission have focused on fast, phasic signals that inhibit target neurons, negatively controlling postsynaptic integration and spike generation. However, GABA can also act via tonic currents that provide a steady-state influence on postsynaptic cells. While tonic GABA largely has been assumed to negatively regulate neuronal activity, recent data from our lab suggests that it may paradoxically enhance excitability of dendrites in cortical pyramidal neurons. Whether this unexpected observation extends throughout the somatodendritic arbor and across cell types is unknown. Additionally, the source of GABA producing tonic currents remains poorly understood, though evidence suggests it may include the same interneurons mediating phasic inhibition. In the present study, we propose a combination of electrophysiology, 2-photon imaging, pharmacology, and optogenetic manipulation both in acute brain slices and in vivo to (1) determine how tonic GABA currents shape dendritic excitability throughout the arbors of cortical pyramidal neurons, (2) identify the neuronal sources of GABA mediating tonic currents in the neocortex, and (3) determine the molecular mechanisms underlying long-term heterosynaptic plasticity of tonic GABAergic signals. Our overall goal is to understand the links between GABAergic transmission and cortical circuit function. We expect that our results will generate new avenues for exploring both the cell biology and functional consequences of GABAergic signaling in the cortex.