Lactate receptor, HCAR1, in neonatal hypoxic-ischemic encephalopathy

Introduction: Hydroxycarboxylic acid receptor 1 (HCAR1) is a G-protein coupled receptor for lactate that is expressed in the brain and plays a role in neuronal excitability, angiogenesis, and repair after injury. Hypoxic-ischemic encephalopathy (HIE) is the most common cause of brain injury and seizures in term neonates. The goal of this study was to describe HCAR1 expression and function in the neonatal brain and further understand its role in HIE. Methods: HCAR1 expression was measured using qRT-PCR in developing mice (postnatal day (p)10, 20, 30, 50). Electrophysiology was used to measure neuronal properties and spontaneous excitatory postsynaptic currents (sEPSC) in hippocampal principal neurons from HCAR1 knockout and wildtype mice when exposed to lactate. Then, p10 HCAR1 knockout and wildtype mice were exposed to hypoxia-ischemia (HI) and placed on electroencephalography (EEG) to compare seizure burden. HCAR1 expression after neonatal HI was measured with PCR. Results: HCAR1 is expressed at p10 at similar levels to adults (n=6/group; 1-way ANOVA, p<0.0004). Lactate decreases amplitudes and sEPSC frequency in wildtype (p<0.0001, p<0.001) but not HCAR1 knockout mice (p<0.26, p=0.91). After HI, HCAR1 knockout mice have higher seizure burden (2318s in WT vs. 6497s in KO (p=0.04)) and behavioral seizure scores (4 in WT vs. 6 in KO (p<0.001)) than wildtypes. HCAR1 expression increased 24h post-HI but drops to below baseline at 48h post-HI. (n=3/group; p=0.02). Conclusion: HCAR1 is expressed on neurons in the developing mouse brain. Lactate decreases neuronal excitability via HCAR1. HCAR1 is upregulated post-HI and mice lacking HCAR1 exhibit worse neonatal HI seizures.