PT - JOURNAL ARTICLE AU - Cahue de Bernardis Murat AU - Ricardo Leao TI - A voltage-dependent depolarization induced by low external glucose in neurons of the nucleus of the tractus solitarius of rats: interaction with K<sub>ATP</sub> channels regulated by external glucose. AID - 10.1101/328658 DP - 2019 Jan 01 TA - bioRxiv PG - 328658 4099 - http://biorxiv.org/content/early/2019/01/21/328658.short 4100 - http://biorxiv.org/content/early/2019/01/21/328658.full AB - The brainstem nucleus of the tractus solitarius (NTS) is an integrative center for autonomic counterregulatory responses to hypoglycemia, NTS neurons can also sense fluctuations in extracellular glucose levels altering their membrane potential. KATP channels links the metabolic status of the neuron to its excitability, but the role of KATP channels in controlling NTS neurons excitability and in sensing extracellular glucose changes is not clear. Here we investigated using in vitro electrophysiological recordings in brainstem slices the influence of KATP channels on the membrane potential of NTS neurons in normoglicemic and hyperglycemic external glucose concentrations, and after switching the external glucose to a hypoglycemic level. We found that in normoglicemic (5 mM) external glucose application of tolbutamide, a KATP blocker, induced a substantial depolarization of most NTS neurons, while application of diazoxide, a KATP opener, hyperpolarized the membrane of all NTS neurons. Interestingly, neurons not responsive to tolbutamide were more depolarized than responsive neurons. In a hyperglycemic solution (10 mM glucose) few neurons depolarized in response to tolbutamide. We found that these neurons were more depolarized than neurons in 5 mM glucose and only the more hyperpolarized responded to tolbutamide. The non-responsive neurons did not respond to tolbutamide even when hyperpolarized. Interestingly application of a low-gucose solution (0.5 mM) did not hyperpolarized the RMP but produced a depolarization in most neurons. This effect was voltage-dependent not seen in neurons more depolarized, but could be observed when the neurons were hyperpolarized. Depolarization by tolbutamide avoided further depolarization by low glucose, unless the membrane was hyperpolarized. Application of 0.5 mM glucose solution in neurons incubated in 10 mM glucose depolarized the membrane only in more hyperpolarized neurons, which responded to tolbutamide, or after membrane hyperpolarization. The effect of glucose was caused by activation of a cationic current with a reversal potential around the potential were the neurons were non-responsive to low glucose. We conclude that NTS neurons present KATP channels open at rest in normoglicemic conditions, and that their state is affected by extracellular glucose. Moreover, NTS neurons depolarize the membrane in response to the application of a low-glucose solution, but this effect is occluded by membrane depolarization triggered by KATP blockage. This suggests a homeostatic regulation of the membrane potential by glucose and a possible mechanism related to hypoglycemia-associated autonomic failure.