S-equol Mitigates Anxiety-like Behaviors Associated with Acute Hyperuricemia by Restoring Neuronal Excitability in the Medial Prefrontal Cortex.

Abstract

Hyperuricemia (HUA) is a prevalent metabolic disorder closely linked to neuropsychiatric symptoms, including emotional disturbances. However, the neural mechanisms underlying this association remain largely unexplored. We established a mouse model of acute HUA by administering potassium oxonate (PO) and hypoxanthine (HX) intraperitoneally to investigate its effects on emotional behaviors and neural activity in the medial prefrontal cortex (mPFC). The HUA mice exhibited typical hyperuricemia and renal morphological abnormalities, along with increased anxiety-like behaviors, but showed no alterations in mechanical/thermal pain sensitivity or depressive-like behaviors. Immunofluorescence c-Fos mapping revealed extensive activation in emotion-related brain regions, such as the mPFC, paraventricular thalamus (PVT), anterior insular cortex (aIC), lateral hypothalamus (LH), and basolateral amygdala (BLA). Whole-cell patch-clamp recordings demonstrated that HUA was associated with reduced intrinsic excitability of mPFC layer V/VI pyramidal neurons, indicated by a lower firing rate, higher rheobase, and decreased membrane input resistance. Additionally, it was associated with alterations in the excitatory/inhibitory (E/I) synaptic balance, including changes the frequency of spontaneous excitatory postsynaptic currents (sEPSCs). Notably, the reduction in mPFC neuronal excitability was comparable between sexes, although female HUA mice displayed less pronounced synaptic alterations in response to HUA. S-equol, a selective estrogen receptor beta ligand, ameliorated anxiety-like behaviors associated with HUA. Electrophysiological analyses revealed that S-equol appeared to restore the intrinsic excitability of mPFC pyramidal neurons in both sexes, although it did not significantly alter E/I synaptic balance. However, its behavioral effects exhibited sex-dependent differences: S-equol significantly ameliorated anxiety-like behaviors in both sexes, with the specific behavioral domains affected varying between males and females. The results suggest that HUA may be linked to anxiety-like behaviors, potentially involving reduced excitability of mPFC pyramidal neurons. Furthermore, S-equol may exert anxiolytic effects in association with restored neuronal excitability, independently of detectable changes in E/I synaptic balance. Together, this study offers new insights into the neurobiological mechanisms underlying HUA-related emotional disorders and identifies sex-specific potential therapeutic targets.