LOSS OF TRESK POTASSIUM CHANNEL ALTERS HIPPOCAMPAL NEURONAL EXCITABILITY, SYNAPTIC PLASTICITY, AND SHAPES BEHAVIOR IN A SEX-SPECIFIC MANNER

The brain’s physiological dynamics depend on ion channel activity, which finely tunes neuronal intrinsic excitability, regulates the excitatory-inhibitory balance, and ultimately shapes behavior. Of particular interest is controlled potassium current leakage via K2P channels. TRESK (K2P18.1) acts as an excitability brake in peripheral nociceptive pathways, yet its function in the brain remains largely unexplored despite its widespread expression throughout the central nervous system. Here, we investigated the functional impact of TRESK on neuronal excitability, synaptic plasticity, and behavior. We combined RNAscope in situ hybridization to identify expression patterns, electrophysiological recordings in acute hippocampal slices to assess neuronal excitability, and a battery of behavioral tests to evaluate the consequences of TRESK deletion on mouse behavior. We observed TRESK mRNA in excitatory and inhibitory neurons throughout the hippocampus, with increased intensity in the CA3 region and dentate gyrus. Field-potential and patch-clamp experiments in TRESK knockout mice revealed that the absence of TRESK increases neuronal excitability in CA3 pyramidal neurons and alters short-term and long-term hippocampal synaptic plasticity. Behavioral analyses uncovered sex-dependent alterations in exploration and emotional regulation, with female TRESK knockout mice exhibiting increased anxiety-like behavior in the elevated zero maze and open field tests. In addition, mice lacking TRESK displayed impaired sociability in the three-chamber social test and enhanced spatial working memory performance in the Y-maze test. These findings support the role of TRESK as a regulator of hippocampal neuronal excitability and lay the groundwork for understanding its contribution to sex-dependent neural dynamics and behavioral changes.