Transient oxygen-glucose deprivation causes region-and cell type-dependent functional deficits in the mouse hippocampus in vitro

Abstract

Neurons are highly vulnerable to conditions of hypoxia-ischemia (HI) such as stroke or transient ischemic at-tacks. Recovery of cognitive and behavioral functions requires re-emergence of coordinated network activity, which, in turn, relies on the well-orchestrated interaction of pyramidal cells (PYRs) and interneurons. We there-fore modelled HI in the mouse hippocampus, a particularly vulnerable region showing marked loss of PYR and fast-spiking interneurons (FSIs) after hypoxic-ischemic insults. Transient oxygen-glucose deprivation (OGD) in ex vivo hippocampal slices led to a rapid loss of neuronal activity and spontaneous network oscillations (sharp wave-ripple complexes; SPW-Rs), and to the occurrence of a spreading depolarization. Following reperfusion, both SPW-R and neuronal spiking resumed, but FSI activity remained strongly reduced compared with PYR. Whole-cell recordings in CA1 PYR revealed, however, a similar reduction of both EPSCs and IPSCs, leaving inhibition-excitation (I/E) balance unaltered. At the network level, SPW-R incidence was strongly reduced and the remaining network events showed region-specific changes including reduced ripple energy in CA3 and in-creased ripple frequency in CA1. Together, our data show that transient hippocampal energy depletion results in severe functional alterations at the cellular and network level. While I/E balance is maintained, synaptic ac-tivity, interneuron spiking and coordinated network patterns remain reduced. Such alterations may be net-work-level correlates of cognitive and functional deficits after cerebral HI.