Regulação de excitabilidade de neurônios do MNTB por receptores mGluR-I: explorando o papel de canais HCN, KIR e TWIK através da eletrofisiologia celular e modelagem computacional

Abstract

The Medial Nucleus of the Trapezoid Body (MNTB) is a synaptic relay in the Superior Olivary Complex (SOC) that plays a role in the early stages of auditory processing by providing precise temporal inhibition to other nuclei, both within and outside the SOC. Among the various biophysical adaptations that MNTB neurons have to faithfully respond to presynaptic activity at high frequencies, some are facilitated by the activation of type I metabotropic glutamate receptors (mGluR-I). Activation of mGluRI generates an inward current observed in voltage-clamp experiments and a depolarization in the resting membrane potential observed in current-clamp experiments. These effects are blocked when accompanied by selective antagonists of HCN channels and by Ba²+ ions, which are capable of blocking KIR and TWIK channels. In this study, we explored the impacts of regulating the currents mediated by these channels on the excitability of the principal neurons of the MNTB. Patchclamp experiments were conducted to characterize the Ih, IKIR, e ITWIK currents, and these components were included in a neuron model of the MNTB adapted from the literature. By manipulating the maximum conductance of these currents to mimic the activation of mGluR-I, it was observed that they are sufficient to suppress failures in action potential generation due to high-frequency synaptic events in the MNTB neuron model of neonatal mice. It was observed that the reduction in failures is caused by an increase in membrane resistance and depolarization of the membrane potential. These effects are more strongly dependent on modulation of the maximum ITWI conductance, followed to a lesser extent by Ih, with only a very minor contribution of IKIR.