Functions for CA1 axo-axonic and basket interneurons in sharp-wave ripple replay and spatial memory

Project Summary: The encoding and consolidation of hippocampus-dependent memories requires temporal coordination of pyramidal neurons in the CA1 region. Specifically, populations of pyramidal neurons organize into sequences representing experience during theta and sharp-wave ripple oscillations. Disruption of the temporal coordination of pyramidal neuron spikes during SWRs, as occurs in pathologies such as epilepsy, results in memory deficits. The cellular and synaptic mechanisms underlying pyramidal neuron spike timing during SWRs with mnemonic functions are largely unknown. Local interneurons, via GABAergic inhibition, are known to regulate CA1 pyramidal neuron spike timing in SWRs. However, there are approximately twenty types of such interneurons, each with distinct anatomy and physiology. How each of these interneurons contributes to spiking activity and memory is unknown. The interneurons hypothesized to have the most precise control over pyramidal neuron spike timing are the axo- axonic (or chandelier) cell, which exclusively synapses directly onto the axon initial segment (AIS), and basket cells which densely synapse on the soma. The functions of these cells in SWR dynamics, replay and spatial memory formation have remained poorly understood, as there have been no reliable markers to genetically access these neurons. In vivo investigations into the effects of axo-axonic and basket cells on pyramidal neuron dynamics in SWRs, replay and their role in spatial memory formation is thus needed. In this proposal, we aim to investigate the role of axo-axonic and basket cells in mnemonic functions of hippocampal circuits, specifically SWRs and replay, and spatial memory formation. Cre drive lines combined with viruses encoding Cre-dependent opsins enable us to manipulate specific interneuron activity in behaving animals. The overarching goal of this proposal is to understand how the unique physiology of axo-axonic and basket cells controls hippocampal circuit activity and pyramidal neuron coordination in network oscillations in support of spatial memory formation.