The role of Kir6.2‐KATP channels in modulating sleep, brain metabolism, and neuronal excitability in AD

Abstract

AbstractBackgroundATP sensitive potassium (KATP) channels act as metabolic sensors to regulate cellular excitability. We recently demonstrated that neuronal KATP channels are composed of Kir6.2 subunits, are highly expressed on excitatory and inhibitory neurons, and are differentially expressed in the Alzheimer’s brain (Grizzanti et al. 2022). Mechanistically, we demonstrated that KATP channels couple changes in cerebral metabolism with neuronal activity and amyloid‐beta (Aβ) release, suggesting a role for KATP channels in Alzheimer’s disease. Here, we extend these studies to explore how KATP channels contribute to excitatory/inhibitory (E/I) balance in the brain to impact sleep and Alzheimer’s pathology. How KATP channels coordinate sleep, metabolism, and neuronal activity was examined using the Kir6.2‐/‐ mice, a mouse model lacking neuronal KATP channel activity.MethodIntracranial biosensors measuring interstitial fluid (ISF) glucose and ISF lactate concurrent with EEG/EMGs were implanted into the hippocampus of wild type (WT) and Kir6.2‐/‐ mice. Diurnal rhythms of ISF glucose, ISF lactate, and EEG/EMG were recorded for 72 hours. Mice were injected with saline, glucose, or glibenclamide to determine effects of metabolic challenges on ISF glucose, ISF lactate, and sleep/wake cycles. Quantitative EEG analysis and sleep staging was performed and correlated with ISF glucose and lactate over the 24 hour light/dark period.ResultWildtype mice have diurnal fluctuations in ISF glucose and lactate, with increases during the dark cycle when mice are awake and decreases in the light cycle when mice are asleep. In Kir6.2‐/‐ mice lacking neuronal KATP channel activity, diurnal fluctuations in ISF glucose and lactate are lost. Kir6.2‐/‐ mice spent more time in NREM sleep and less time awake than WT mice. Furthermore, reductions in absolute EEG power suggest changes in the brain’s E/I balance. Lastly, Kir6.2‐/‐ mice were unresponsive to metabolic challenges, demonstrating that ISF lactate, a metabolic trigger for wakefulness, is controlled by KATP channels.ConclusionWe describe the role of neuronal KATP channels as metabolic sensors in coordinating sleep/wake architecture in mice. Ongoing studies are exploring the impact of KATP channels on sleep and brain excitability in AD.