Binding of HCN channels to GABAB receptors in dopamine neurons of the VTA limits synaptic inhibition and prevents the development of anxiety

Abstract

During GABAergic synaptic transmission, G protein-coupled GABA_B receptors (GBRs) activate K⁺ channels that prolong the duration of inhibitory postsynaptic potentials (IPSPs). We now show that KCTD16, an auxiliary GBR subunit, anchors hyperpolarization-activated cyclic nucleotide-gated (HCN) channels containing HCN2/HCN3 subunits to GBRs. In dopamine neurons of the VTA (DA^VTA neurons), this interaction facilitates activation of HCN channels via hyperpolarization during IPSPs, counteracting the GBR-mediated late phase of these IPSPs. Consequently, disruption of the GBR/HCN complex in KCTD16^-/- mice leads to prolonged optogenetic inhibition of DA^VTA neuron firing. KCTD16^-/- mice exhibit increased anxiety-like behavior in response to stress - a behavior replicated by CRISPR/Cas9-mediated KCTD16 ablation in DA^VTA neurons or by intra-VTA infusion of an HCN antagonist in wild-type mice. Our findings support that the retention of HCN channels at GABAergic synapses by GBRs in DA^VTA neurons provides a negative feedback mechanism that restricts IPSP duration and mitigates the development of anxiety.

Keywords: GABA-A; GABA-B; HCN2; Hyperpolarization-activated cyclic nucleotide-gated channels; Late IPSP; Optogenetic inhibition; Slow IPSP.