Grant: Operating Grant

How circuits of neurons process information depends on the dynamic dialogue between two network elements: principal cells and local circuit inhibitory interneurons. As network gatekeepers, GABAergic inhibitory interneurons control all stages of information processing by principal neurons, from signal integration to generating spikes and synchronized network oscillations. To perform these precise operations, inhibitory interneurons must be tightly organized in functional ensembles. In the hippocampus, the brain structure involved in learning and memory, a specific population of inhibitory interneurons selectively innervates other GABAergic cells, and may provide the cellular basis for such higher-level control of network computations. However, the physiological properties and the role of these cells in the local circuit dialogue remain unknown. We propose that the specific physiological organization of these interneuron-specific interneurons (ISIs) allows them to efficiently integrate multiple cortical and subcortical inputs and to act as a fine-tuning device sculpting the inhibition received by principal cells. We will use a combination of whole-cell patch-clamp electrophysiology, two-photon microscopy, and pharmacology in acute slices of mouse hippocampus to investigate: (1) how ISIs integrate signals and produce spikes; (2) how their signal integration is affected by the activation of subcortical inputs; (3) how connections between inhibitory interneurons are modified by changes in activity; and (4) how the inhibitory control of local circuit inhibition directs the network activity. This investigation should provide essential information about the functional organization of inhibitory interneurons specialized to control network inhibition. It will also yield new important insights into how the interactions between specific neural elements form working neural circuits, and how these may break down in brain disorders.