| First Author | P?rez-Garci E | Year | 2025 |
| Journal | Neurobiol Dis | Volume | 206 |
| Pages | 106831 | PubMed ID | 39914775 |
| Mgi Jnum | J:371858 | Mgi Id | MGI:8160737 |
| Doi | 10.1016/j.nbd.2025.106831 | Citation | Perez-Garci E, et al. (2025) Binding of HCN channels to GABA(B) receptors in dopamine neurons of the VTA limits synaptic inhibition and prevents the development of anxiety. Neurobiol Dis 206:106831 |
| abstractText | 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. |
