Transient Receptor Potential Melastatin 2 Thermosensitive Neurons in the Preoptic Area Involved in Menopausal Hot Flashes in Ovariectomized Mice

INTRODUCTION: Menopausal hot flashes are related to hypothalamic preoptic area (POA) dysfunction. Thermosensitive transient receptor potential channels (ThermoTRPs) are involved in temperature sensing and regulation of thermosensitive neurons (TSNs) in the POA. Whether ThermoTRP-TSNs in the POA, particularly the non-noxious thermoreceptor, transient receptor potential melastatin 2 (TRPM2), are involved in the occurrence of hot flashes is still unclear. METHODS: Twenty wild-type and 50 Trpm2-Cre adult female mice were randomly divided into sham (SHAM) and ovariectomy (OVX) groups. In the POA, ERα, ERβ, GPR30, TRPA1, TRPM8, TRPM2, and TRPV1 expression was detected by Western blot or/and quantitative real-time polymerase chain reaction and the number of TSNs expressing TRPM2 (TRPM2-TSNs) by immunofluorescence. Before and after TRPM2-TSN activation/inhibition, back (BST) and tail skin temperature (TST) and the proportion of glutamatergic and GABAergic neurons among TRPM2-TSNs were recorded. RESULTS: Compared with SHAM, the expression of ERα, ERβ, TRPM2, and TRPM8 in the POA of the OVX group decreased, with a significantly larger change range for TRPM2 than TRPM8. In addition, the number of TRPM2-TSNs showing TRPA1, TRPM8, and TRPV1 expression in the OVX group decreased, and the proportion of glutamatergic and GABAergic neurons in TRPM2-TSNs decreased and increased, respectively. Meanwhile, BST and TST increased. After activating or inhibiting TRPM2-TSNs, the proportions of glutamatergic and GABAergic neurons in TRPM2-TSNs changed, along with the BST and TST. CONCLUSION: In menopause, the abnormal quantity and function of TRPM2-TSNs in the POA is key for the development of hot flashes, characterized by an imbalance in heat dissipation and production due to the corresponding imbalance in glutamatergic and GABAergic neurons.