Plasticity of TRPV1‐dependent Neurotransmission in the Paraventricular Nucleus of db/db Mice

Abstract

Transient receptor potential vanilloid type 1 (TRPV1) has been shown to play a role in the modulation of glucose homeostasis. Preautonomic, liver‐related neurons in the paraventricular nucleus (PVN) of the hypothalamus contribute to the regulation of sympathetic and parasympathetic outflow to the liver. Our previous findings demonstrated that liver‐related PVN neurons are controlled by TRPV1‐dependent excitatory neurotransmission. In this study, liver‐related PVN neurons were identified with a retrograde, trans‐neuronal viral tracer and whole‐cell patch‐clamp recordings were conducted. We tested the hypothesis that the TRPV1‐dependent synaptic control of liver‐related PVN neurons is reduced in db/db mice. Application of the exogenous TRPV1 agonist, capsaicin (1μM) increased the average frequency of miniature excitatory post‐synaptic currents (mEPSCs) in liver‐related PVN neurons from lean mice. In contrast, in db/db mice capsaicin application did not change the overall frequency of mEPSCs. Capsaicin did not alter the frequency of miniature inhibitory post‐synaptic currents (mIPSCs) neither in lean or db/db mice. We did not observe significant difference in the basal frequency of mEPSCs and mIPSCs in liver‐related PVN neurons of lean and db/db mice. On the other hand, the amplitude of mIPSCs was smaller in liver‐related PVN neurons of db/db mice compared with lean mice. GABAA‐mediated inhibitory tonic currents as bicuculline‐dependent inward shift of the holding current were also revealed in liver‐related PVN neurons. Our data did not show difference in the magnitude of tonic inhibition between the groups. Together, this study suggests that the TRPV1‐dependent control of liver‐related PVN neurons is diminished in db/db mice. These findings are consistent with our previous data demonstrating synaptic plasticity of hypothalamic autonomic circuits in hyperglycemic conditions, and further suggest dysregulation of neuronal activity at the level of the PVN in obese‐diabetic state.Support or Funding InformationSupported by NIDDK R01DK099598