RT Journal Article SR Electronic T1 Inhibition is the hallmark of CA3 intracellular dynamics around awake ripples JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.04.20.440699 DO 10.1101/2021.04.20.440699 A1 Koichiro Kajikawa A1 Brad K. Hulse A1 Athanassios G. Siapas A1 Evgueniy V. Lubenov YR 2021 UL http://biorxiv.org/content/early/2021/04/22/2021.04.20.440699.abstract AB Hippocampal ripples are transient population bursts that structure cortico-hippocampal communication and play a central role in memory processing. However, the mechanisms controlling ripple initiation in behaving animals remain poorly understood. Here we combine multisite extracellular and whole cell recordings in awake mice to contrast the brain state and ripple modulation of subthreshold dynamics across hippocampal subfields. We find that entorhinal input to DG exhibits UP and DOWN dynamics with ripples occurring exclusively in UP states. While elevated cortical input in UP states generates depolarization in DG and CA1, it produces persistent hyperpolarization in CA3 neurons. Furthermore, growing inhibition is evident in CA3 throughout the course of the ripple buildup, while DG and CA1 neurons exhibit depolarization transients 100 ms before and during ripples. These observations highlight the importance of CA3 inhibition for ripple generation, while pre-ripple responses indicate a long and orchestrated ripple initiation process in the awake state.Competing Interest StatementThe authors have declared no competing interest.