Endogenous Recovery of Hippocampal Function Following Global Cerebral Ischemia in Juvenile Female Mice Is Influenced by Neuroinflammation and Circulating Sex Hormones

Cardiac arrest (CA)-induced global cerebral ischemia (GCI) in childhood often results in learning and memory deficits. We previously demonstrated in a murine CA and cardiopulmonary resuscitation (CA/CPR) mouse model that a cellular mechanism of learning and memory, long-term potentiation (LTP), is acutely impaired in the hippocampus of juvenile males, correlating with deficits in memory tasks. However, little is known regarding plasticity impairments in juvenile females. We performed CA/CPR in juvenile (P21-25) female mice and used slice electrophysiology and hippocampal-dependent behavior to assess hippocampal function. LTP and contextual fear were impaired 7 days after GCI and endogenously recovered by 30 days. LTP remained impaired at 30 days in ovariectomized females, suggesting the surge in gonadal sex hormones during puberty mediates endogenous recovery. Unlike juvenile males, recovery of LTP in juvenile females was not associated with BDNF expression. NanoString transcriptional analysis revealed a potential role of neuroinflammatory processes, and specifically Cd68 pathways, in LTP impairment and hormone-dependent recovery. This was confirmed with staining that revealed increased Cd68 expression in microglia within the hippocampus. We were able to restore LTP in ovariectomized females with chronic and acute PPT administration, implicating estrogen receptor alpha in recovery mechanisms. This study supports a mechanism of endogenous LTP recovery after GCI in juvenile female mice, which differs mechanistically from juvenile males and does not occur in adults of either sex.