Therapeutic hypothermia does not prevent dysmaturity of medial ganglionic eminence-derived interneurons in the dorsal hippocampus after neonatal hypoxia-ischemia.

INTRODUCTION: Neonatal hypoxic-ischemic (HI) brain injury results in a persistent deficit of hippocampal parvalbumin (PV)+ interneurons (INs), despite therapeutic hypothermia (TH). Since INs from the medial ganglionic eminence (MGE) begin expressing PV around time of injury, we hypothesized that HI injury would result in maturational arrest of INs persisting through adulthood and resulting in memory deficits. METHODS: Following HI at P10, mice were randomized to normothermia (36 °C, NT) or hypothermia (31 °C, TH) with anesthesia-exposed littermates as shams. Hippocampus was evaluated at P11, P18, and P40 for PV, SST, SAtb1, GFAP, Kv3.1b, and Kv3.2 (IF-IHC), electrical phenotyping and mIPSC (patch clamping), and RNA (real time RT PCR) and protein (western blot). Y-maze task and open field were performed for the P40 cohort. RESULTS: The number of SAtb1+ GE-derived INs was lower at P18 in injured hippocampus compared to sham. The proportion of SAtb1+ INs without PV or SST expression by P18 was greater in HI-injured hippocampi, regardless of TH, a difference persisting to P40. Although HI-injured PV+ SAtb1+ INs demonstrated dendritic simplification and decreased Kv3.1b levels despite TH thru P40, they still achieved mature fast-spiking electrical phenotype by P18. By P40, deficits in Kv3.2 along with in Kv3.1b were demonstrated in HI-injured PV+ INs and attenuated by TH. Decreased mIPSC amplitude was documented at P40. Higher proportion of SAtb1+ INs negative for PV or SST correlated with worse spatial memory. CONCLUSIONS: Neonatal HI brain injury leads to dysmature GE-derived INs in the hippocampus, which persists to adulthood and not prevented by TH. Surviving GE-derived SAtb1+ INs may serve as a target to recover GABAergic deficits after HI injury in the era of TH to treat neonatal HI brain injury.