PHYSIOLOGICAL ROLE OF THE AMYLOID PRECURSOR PROTEIN (APP) IN LOCAL CIRCUITS WITHIN HIPPOCAMPAL CA3

The full-length amyloid precursor protein (APP), a key player in Alzheimer’s disease (AD), is ubiquitously expressed in a large majority of neurons, including GABAergic interneurons (INTs). Importantly, local inhibition by specific interneurons subpopulations influence brain rythms and recent studies have provided evidence of disrupted hippocampal plasticity in conditional APP KO of GABAergic forebrain neurons (Mehr et al, 2020). However, the role of APP within hippocampal INTs to balance neuronal activity remains unclear. We investigate the physiological function of APP at inhibitory synapses onto CA3 pyramidal cells (PCs) at both cellular and circuit levels. By combining ex vivo electrophysiology and neuronal morphological reconstruction, we observed that selective deletion of APP and the related protein APLP2 in CA3 INTs modified the kinetics (i.e. amplitude and rise time) of spontaneous inhibitory currents in CA3 PCs. Using a patch-sequencing approach we categorized INTs into different clusters, possibly highlighting INTs subtypes. We noticed subtle significant differences in cell excitability and dendritic complexity within one cluster, between APP/APLP2dKO and control CA3 INTs. We also performed silicon probe in vivo recordings within the CA3 region of awake mice to investigate potential effects of APP/APLP2 deletion on the global circuit activity and cell synchronicity. This allows exploring the oscillatory components and the spiking activity of putative CA3 PCs and INTs. Our work helps to better understand the physiological contribution of APP on global neuronal activity and excitatory/inhibitory balance within hippocampal circuits, which are impaired in AD.