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

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378041%3A_____%2F25%3A00605836" target="_blank" >RIV/68378041:_____/25:00605836 - isvavai.cz</a>
Result on the web
<a href="https://www.sciencedirect.com/science/article/pii/S0969996125000476" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0969996125000476</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.nbd.2025.106831" target="_blank" >10.1016/j.nbd.2025.106831</a>

Result language
angličtina
Original language name
Binding of HCN channels to GABAB receptors in dopamine neurons of the VTA limits synaptic inhibition and prevents the development of anxiety
Original language description
During GABAergic synaptic transmission, G protein-coupled GABAB 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 (DAVTA 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 DAVTA neuron firing. KCTD16−/− mice exhibit increased anxiety-like behavior in response to stress - a behavior replicated by CRISPR/Cas9-mediated KCTD16 ablation in DAVTA 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 DAVTA neurons provides a negative feedback mechanism that restricts IPSP duration and mitigates the development of anxiety.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30103 - Neurosciences (including psychophysiology)

Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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