Role of CCK-positive perisomatic inhibitory neurons in the generation of normal and pathological network oscillations in the mouse hippocampus

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Perisomatic inhibition plays a key role in synchronizing network activity in many brain regions. In the last few decades, the rodent hippocampus has become an important model for studying synaptic inhibition andplasticity as fundamental mechanisms underlying network oscillations. Perisomatic inhibition of hippocampal principal neurons is mainly provided by parvalbumin (PV)-positive and cholecystokinin(CCK)-positive interneurons (INs). Both types of IN have largely similar afferent and efferent connectivity and act synergistically in providing feedback and feedforward inhibition. They differ, however, in their involvement in oscillatory activity. PV-positive cells arecruciallyinvolved in high-frequency activity (sharp wave ripples (SPWRs) and gamma oscillations) while CCK-positive INs are involved in low frequency theta oscillations. The reasons for this differential behavior are not clear. Here we propose that a unique property of CCK-positive INs, namely asynchronous releaseof GABA, is a fundamental mechanismunderlying their role in local network activity. We suggest that this feature (1) diminishes their involvement in high frequency events, (2) makes them suitable for generation of low frequency oscillations, and (3) is crucial in prevention of epileptiform activity. In the proposed project, we will study the role of CCK-positive Ins and asynchronous GABA release in the generation and termination of normal and pathological hippocampal network oscillations. We will manipulate GABA release from CCK IN terminals in vitro, using a variety of modern tools. In wild-type mice, the activity of the two types of INwillbe selectively modulated by agonists or antagonists of presynaptically located G-protein-coupled receptors, by introductionof calcium buffers via a patch clamp pipette, and by interfering with the presynaptic calcium extrusion pumps. In mice with specifically targeted CCK-positive INs, viral vectors will be used to introduce chemogenetic agents (ivermectin-sensitive mutant GlyR-alpha1 receptors), genetically encoded calcium buffers, or optogenetictools. Together with electrophysiological analysis of cellular and network behavior, these approaches will allow us to selectively evaluatethe differential involvement of CCK-positive INs in the generation of hippocampal rhythms in normal and pathological states.