FUNCTIONAL IMPACTS OF mGluR-I ACTIVATION ON MNTB

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. Activation of mGluR-I generates an inward current observed in voltage-clamp experiments and a depolarization in the resting membrane potential observed in current-clamp experiments, as indicated in previous studies.  These effects are blocked when accompanied by selective antagonists of Hyperpolarization-activated channels (HCN), and by Ba²+ ions, which are capable of blocking Inward-rectifier potassium channels (KIR), Two-pore-domain potassium channels (TWIK) and Muscarinic potassium channels (Kv7). 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 through computational modeling and simulation based on whole-cell patch-clamp experimental data. Our previous model was expanded to better describe HCN gating dynamics based on voltage-clamp experiments, and to add Kv7 component to the barium sensitive current adjustment, along with KIR and TWIK. Four voltage-dependent potassium channels (Kv1-4) and one voltage-dependent sodium channel taken from literature specifically for MNTB were added to the model. Parameters of these mechanisms were optimized in order to make the model reproduce experimental current-clamp characteristics. A synaptic conductance mechanism taken from literature was added to the model and adjusted to mimics spontaneous events observed in our experiments. By manipulating the maximum conductance of these currents to mimic the activation of mGluR-I (enhancement of HCN, and block of KIR, TWIK and Kv7), it was observed that they are sufficient to suppress failures in action potential generation due to high-frequency synaptic events in the MNTB model. 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 TWIK conductance, followed by Kv7, and to a lesser extent by HCN, with only a very minor contribution of KIR.

This work was supported by Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG – APQ-00842-23).