Work

GABA B receptor/HCN channel complexes in VTA dopamine neurons limit synaptic inhibition and prevent anxiety-like behavior

Year: 2021

Type: preprint

Abstract: Aversive stimuli inhibiting dopamine neurons in the ventral tegmental area (DA VTA neurons) induce anxiety-like behaviors. The inhibition of DA VTA neurons is prolonged by GABA B receptor (GBR)-activated K + -currents, which exhibit a rapid desensitization of unknown physiological relevance. We now report that GBRs associate via auxiliary KCTD16 subunits with HCN channels, which facilitates activation of hyperpolarization- activated currents ( I h ) by GBR-activated K + currents. Activation of I h underlies rapid K + current desensitization in DA VTA neurons and limits GBR-mediated inhibition. Disruption of the GBR/HCN complex in KCTD16 -/- mice or blockade of I h prolongs optogenetically driven inhibition of DA VTA neuron firing. KCTD16 -/- mice exhibit an increased anxiety-like behavior in response to stressful stimuli, which is reproduced by in vivo CRISPR/Cas9-mediated KCTD16 ablation in DA VTA neurons or intra-VTA infusion of HCN antagonist to wild-type mice. Our data reveal that GBR-induced I h protect DA VTA neurons from prolonged GBR- mediated inhibition in response to stressors, which moderates anxiety-like behaviors.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/2021.09.27.461912