HCAR1-mediated lactate signaling modulates motor behavior and regulates spontaneous firing in Purkinje cells

Lactate modulates several phenomena ranging from gene transcription to plasticity. Through its specific GPCR receptor HCAR1, lactate acts as a signaling molecule modulating neuronal excitability. Silencing lactate signaling promotes anxiety-like behavior and worsens epileptic seizures, highlighting the central role of HCAR1 in brain function. HCAR1 expression in the cerebellum supports the role of the receptor in motor coordination. Early experimental evidence suggesting HCAR1 expression in cerebellar Purkinje cells (PCs) together with its ability to modulate neuronal excitability qualifies the receptor as a possible modulator of PC activity with important implications for cerebellar-mediated diseases. This hypothesis was investigated using behavioral analysis and ex vivo electrophysiology that showed gait instability and motor learning defects in HCAR1 knockout mice associated with increased PC firing. We identified HCN channels as the downstream target of HCAR1. We conclude that lactate signaling is a modulator of PC excitability and revealed the HCAR1 role in motor behavior.