Low-glucose-sensitive TRPC6 dysfunction drives hypoglycemia-induced cognitive impairment in diabetes

Area of Science:

• Neuroscience
• Endocrinology
• Mitochondrial Biology

Background:

• Recurrent moderate hypoglycemia (RH) is a significant risk factor for cognitive impairment and dementia in diabetic patients.
• Transient receptor potential canonical channel 6 (TRPC6) is implicated in Alzheimer's disease and its expression is sensitive to glucose levels.

Purpose of the Study:

• To determine if RH affects TRPC6 expression in the brain.
• To investigate if TRPC6 dysfunction contributes to hypoglycemia-associated cognitive impairment in diabetes.
• To elucidate the underlying molecular mechanisms.

Main Methods:

• Neuronal death, brain activity, and cognitive function were assessed in mice using histological staining, in vivo two-photon Ca2+ imaging, and behavioral tests.
• Mitochondrial structure and function were analyzed via high-resolution respirometry and transmission electron microscopy.
• Intracellular calcium and molecular pathways were examined using calcium imaging and molecular biology techniques.

Main Results:

• RH specifically reduced hippocampal TRPC6 expression in diabetic mice, leading to neuron loss and cognitive impairment.
• TRPC6 knockout mimicked RH-induced cognitive deficits; TRPC6 activation with hyperforin ameliorated these deficits.
• TRPC6 inhibited mitochondrial fission via AMPK activation, requiring calcium influx, and TRPC6 dysfunction correlated with cognitive impairment in diabetic patients.

Conclusions:

• TRPC6 is a crucial, hypoglycemia-sensitive cation channel in the brain.
• TRPC6 represents a promising therapeutic target for preventing cognitive impairment associated with recurrent hypoglycemia in diabetes by modulating mitochondrial dynamics.