Recurrent moderate hypoglycemia (RH), a major adverse effect of hypoglycemic therapy in diabetic patients, is one of the main risk factors for cognitive impairment and dementia. Transient receptor potential canonical channel 6 (TRPC6) is a potential therapeutic target for Alzheimer's disease (AD) and its expression is highly regulated by glucose concentration.

To investigate whether RH regulates the expression of TRPC6 in brain and whether TRPC6 dysfunction can drive hypoglycemia‐associated cognitive impairment in diabetes, and reveal the underlying mechanism.

Histological staining, in vivo two‐photon Ca²⁺ imaging, and behavioral tests were used to measure neuronal death, brain network activity, and cognitive function in mice, respectively. High‐resolution respirometry and transmission electron microscope were used to assess mitochondrial structure and function. Intracellular calcium measurement and molecular biology techniques were conducted to uncover the underlying mechanism.

Here, we report that the expression of TRPC6 in hippocampus was specifically repressed by RH in streptozocin‐induced type 1 diabetic mice, but not in nondiabetic mice. TRPC6 knockout directly leads to neuron loss, neuronal activity, and cognitive function impairment under diabetic condition, the degree of which is similar to that of RH. Activation of TRPC6 with hyperforin substantially improved RH‐induced cognitive impairment. Mechanistically, TRPC6 inhibited mitochondrial fission in the hippocampus of diabetic mice undergoing RH episodes by activating adenosine 5‘‐monophosphate‐activated protein kinase, and TRPC6‐mediated cytosolic calcium influx was required for this process. Clinically, dysfunction of TRPC6 was closely associated with cognitive impairment in type 2 diabetic patients with RH.

Our results indicate that TRPC6 is a critical sensitive cation channel to hypoglycemia and is a promising target to prevent RH‐induced cognitive impairment by properly orchestrating the mitochondrial dynamics in diabetic patients.