¹Luis A. Rojas-Colón, ¹Arelys A. Angueira-Laureano, ² David E. Rivera-Aponte, ²Misty J. Eaton, ^2,3Serguei N. Skatchkov, ^1,2,4Miguel P. Méndez-González

1 Department of Natural Sciences, University of Puerto Rico, Aguadilla, PR 00604-6150, USA

2 Department of Biochemistry, Universidad Central del Caribe, School of Medicine, Bayamón, PR 00960-6032, USA

3 Departments of Physiology and Biochemistry Universidad Central del Caribe, School of Medicine, Bayamón, PR 00960-6032, USA

4 Department of Sciences and Technology, Antilles Adventist University, Mayaguez, PR 00680, USA

INTRODUCTION: Epilepsy is one of the most common neurological disorders in the U.S. and is characterized by neuronal hyperactivity. Diabetic patients are at increased risk of suffering from epilepsy, increasing their morbidity and mortality. Several reports have identified sex differences in epilepsies and seizure conditions. However, the association of sex differences between epilepsy and diabetes has yet to be elucidated. One of the factors that may contribute to epileptiform activity is the accumulation of extracellular potassium [K⁺] in active synaptic areas. Astrocytes are cells that provide support, deliver nutrients to neuronal circuits, and maintain extracellular ion balance utilizing a wide variety of channels and transporters. One important well-characterized process that relates to epilepsy is the regulation of [K⁺]_o. The Kir4.1 inwardly rectifying potassium channel (Kir4.1) located in astrocytes surrounding synapses largely carries out the process of potassium buffering. Mutations or variations of Kir4.1 channels have been described in human epilepsy. The present study aims to determine if the downregulation of functional astrocytic Kir4.1 channels occur in the brains of type 2 diabetic male and female mice and if this reduction could influence hippocampal neuronal hyperexcitability in a sex-dependent manner.

METHODS: Using whole-cell patch clamp recording in hippocampal brain slices from diabetic male and female mice, we determined the electrophysiological properties of stratum radiatum astrocytes.

RESULTS: We observed that in both sexes, hippocampal astrocytic Kir4.1 channels were functionally downregulated as evidenced by depolarized membrane potential, impaired potassium uptake capabilities, and reduced barium-sensitive Kir currents. However, astrocytes from diabetic male mice blocked significantly fewer barium currents than their female counterparts.

CONCLUSION: Our data suggest that during hyperglycemia, astrocytes are less functional in male diabetic mice when compared to female diabetics. In general, diabetes may increase seizure susceptibility by impairing the astrocytic ability to maintain proper extracellular homeostasis.

IACUC APPROVAL NUMBER: 051-2023-31-01-PHA

ACKNLOWLEDGMENTS: We thank Betzaida Torres and Miriam Objio for the technical assistance. This work was supported by the following funding sources: NIH P20 GM103475-19, American Diabetes Association 1-19-IBS-300, NIH-NINDS R15-NS116478, NIH-NINDS SC2NS124907, NIH-NINDS NS124907 and NIH-NIMHD G12MD007583.