TRPA1 Receptor Expressed by the Edinger-Westphal Nucleus (EWcp) is Involved in Stress Adaptation

Abstract

<b>Abstract ID 16795</b> <b>Poster Board 145</b> The Transient Receptor Potential Ankyrin 1 (TRPA1) non-selective cation channel expressed by the primary sensory neurons mediates pain sensation and neurogenic inflammation. It is also expressed in the brain, but little is known about its specific physiological and pathological roles. Our earlier studies using TRPA1 knockout mice revealed that the genetic lack of the receptor inhibits the neurodeneration in murine models of multiple sclerosis, Alzheimer disease and aging.TRPA1 mRNA expression was previously shown in mouse and human EWcp urocortin1 (UCN1) positive neurons and reacted to chronic variable stress. In the present study we hypothesized that TRPA1 receptor mediated events may participate in posttraumatic stress disorder (PTSD). A selective, covalent TRPA1 agonist, JT010 was used on acute EWcp slices of C57BL/6J male mice for electrophysiological measurements. Male Trpa1 WT and KO mice were used in a PTSD model, single prolonged stress (SPS). Two weeks later the behavioral tests, forced swim test (FST) and restraint were performed. The Trpa1 and Ucn1 mRNA expression and the UCN1 peptide content were visualized by RNAscope in situ hybridization combined with immunohistochemistry in EWcp. JT010 activated TRPA1 channels of urocortinergic cells in acute slices proving its functionality. Trpa1 KO animals showed significantly reduced immobility after SPS compared to WT mice, both in the FST and restraint stress. Expession of Trpa1 mRNA was significantly decreased in EWcp of WT animals in response to SPS. Higher basal Ucn1 mRNA expression was observed in the EWcp of KO animals, that was not affected by SPS exposure. Urocortinergic cells of WT animals responded to SPS with strong increase of UCN1 peptide content compared to the controls, however, this was not noticeable in the KO animals. We proved the presence of functional TRPA1 receptors on EWcp/UCN1 neurons. Since the decreased Trpa1 mRNA expression in the SPS model of PTSD associated with increased neuronal UCN1 peptide content we presume that TRPA1 participates in the regulation of stress adaptation and plays role in the development of PTSD. TKP2021-EGA-16 support provided from the National Research, Development and Innovation Fund of Hungary, financed under the EGA 16 funding scheme. RRF-2.3.1-21-2022-00015 support provided by the European Union. Hungarian Brain Research Program 3.0 (NAP 3.0) 2022-2025.