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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Neurobiology of Disease

ISSN

0969-9961

e-ISSN

1095-953X

Svazek periodika

206

Číslo periodika v rámci svazku

March

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

41

Strana od-do

106831

Kód UT WoS článku

001425309100001

EID výsledku v databázi Scopus

2-s2.0-85217010249