Entorhinal Cortex Hyperexcitability Drives Selective Hippocampal Injury and Cognitive Impairment After Global...

The hippocampus is highly susceptible to global cerebral ischemia, yet the contribution of extrahippocampal regions to this vulnerability remains poorly defined. In particular, afferent inputs to the hippocampus, such as those from the entorhinal cortex (EC), have received limited investigation in the context of ischemic brain injury.

Global cerebral ischemia was performed using a 2-vessel occlusion methods in mice. In vitro electrophysiological techniques were used to detect the excitability of EC during ischemia-reperfusion and after chemogenetic inhibition. Cell damage in the hippocampus was examined by the immunofluorescence method. A behavioral test battery comprising the Barnes maze, novel object recognition, and contextual fear conditioning was conducted to assess cognitive performance.

Immunofluorescence assay and electrophysiological recordings revealed significant hyperexcitability in the EC during the reperfusion phase after global cerebral ischemia, manifested by increased c-Fos expression, enhanced frequency of evoked action potentials, a more depolarized resting membrane potential and shortened latency of current-evoked action potentials. Notably, chemogenetic inhibition of EC activity attenuated hippocampal synaptic plasticity deficits, reduced neuronal cell loss, and improved cognitive performance following ischemia.

These findings identify the EC as a critical upstream modulator of hippocampal vulnerability to global cerebral ischemia and suggest that targeting EC excitability may provide a novel therapeutic avenue for ischemia-related cognitive impairment.