Subpopulation of CA3 pyramidal cells drive hippocampal sharp wave-ripple complex

• Applicants: Dr. Tamar Dugladze; Professor Dr. Tengis Gloveli
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 430281601

Sharp wave-ripple (SWR) activity, a prominent hippocampal network rhythm relevant for memory consolidation, are generated in the neuronal circuits of hippocampal CA3 area, but the source of the intrinsic excitatory drive initiating these population events is unclear. Two functional sub-groups of principal excitatory neurons were defined so far according to their firing behavior during SWRs in vivo and in vitro: ‘participating’ and ‘non-participating’ pyramidal cells (PCs). Our working hypothesis is that a third functional PC group exists, which can initiate and maintain the SWR events by providing an excitatory drive to the local network (‘network drive PCs’, ‘ndPCs’). Indeed, in pilot experiments, we have detected deep PCs of CA3a/b subarea, which fired during almost all SWR events, first ramping up their activity and are active throughout the event-duration. The aim of the current proposal is to analyze physiological, anatomical and molecular properties of ndPCs. To achieve these goals, we aim to apply combined in vitro and in vivo electrophysiological, immunohistochemical and morphological approaches. We will characterize the intrinsic and synaptic properties of ndPCs in the active network in vitro, and compare them with those of other PCs, to determine if these properties underlie their higher excitability. In particular, we hypothesize that the GABAA-receptor mediated inhibition in ndPCs is depolarizing. Therefore, we will determine the expression level of KCC2 cotransporter to clarify whether it´s reduced expression in ndPCs may account for a more depolarizing reversal potential of SWR-associated synaptic events. In addition, we will examine the maturation of CA3 PCs using the microtubule-associated protein doublecortin and a transgenic mouse line, addressing the question whether ndPCs represent early-maturating cells, similar to early-generated ‘hub’ cells relevant for maturating network activities. Furthermore, given the putative distinct role of CA3 PCs in the active network, we will test whether a specific axonal activity pattern support the ndPC function by applying dual axonal and somatic recordings. Finally, we will examine SWR associated PC activity in anaesthetized mice, and analyze the information encoding potential and spatial modulation of ndPCs in awake behaving head-fixed mice. These physiological and immunohistochemical in vitro and in vivo investigations will be complemented by morphological analysis to support the distinction of ndPCs. Our results will make an important contribution to the understanding of the mechanisms of SWR generation, a network activity pattern essential for memory consolidation.

• DFG Programme: Research Grants