Binding of HCN channels to GABAB receptors in dopamine neurons of the VTA limits synaptic inhibition and prevents the development of anxiety
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-03-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000476 |
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| author | Enrique Pérez-Garci Kateryna Pysanenko Giorgio Rizzi Florian Studer Daniel Ulrich Thorsten Fritzius Simon Früh Alessandra Porcu Valérie Besseyrias Adolf Melichar Martin Gassmann Tania Rinaldi Barkat Rostislav Tureček Kelly R. Tan Bernhard Bettler |
| author_facet | Enrique Pérez-Garci Kateryna Pysanenko Giorgio Rizzi Florian Studer Daniel Ulrich Thorsten Fritzius Simon Früh Alessandra Porcu Valérie Besseyrias Adolf Melichar Martin Gassmann Tania Rinaldi Barkat Rostislav Tureček Kelly R. Tan Bernhard Bettler |
| author_sort | Enrique Pérez-Garci |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-b1882815549048c6879b2d8fd8da9ca6 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-b1882815549048c6879b2d8fd8da9ca62025-02-09T04:59:43ZengElsevierNeurobiology of Disease1095-953X2025-03-01206106831Binding of HCN channels to GABAB receptors in dopamine neurons of the VTA limits synaptic inhibition and prevents the development of anxietyEnrique Pérez-Garci0Kateryna Pysanenko1Giorgio Rizzi2Florian Studer3Daniel Ulrich4Thorsten Fritzius5Simon Früh6Alessandra Porcu7Valérie Besseyrias8Adolf Melichar9Martin Gassmann10Tania Rinaldi Barkat11Rostislav Tureček12Kelly R. Tan13Bernhard Bettler14Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, SwitzerlandDepartment of Auditory Neuroscience, Institute of Experimental Medicine, CAS, Videnska 1083, 14220 Prague 4, Czech RepublicBiozentrum, University of Basel, Spitalstrasse 41, CH-4056 Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, SwitzerlandDepartment of Auditory Neuroscience, Institute of Experimental Medicine, CAS, Videnska 1083, 14220 Prague 4, Czech RepublicDepartment of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, SwitzerlandDepartment of Auditory Neuroscience, Institute of Experimental Medicine, CAS, Videnska 1083, 14220 Prague 4, Czech RepublicBiozentrum, University of Basel, Spitalstrasse 41, CH-4056 Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S0969996125000476GABA-AGABA-BHCN2Hyperpolarization-activated cyclic nucleotide-gated channelsLate IPSPSlow IPSP |
| spellingShingle | Enrique Pérez-Garci Kateryna Pysanenko Giorgio Rizzi Florian Studer Daniel Ulrich Thorsten Fritzius Simon Früh Alessandra Porcu Valérie Besseyrias Adolf Melichar Martin Gassmann Tania Rinaldi Barkat Rostislav Tureček Kelly R. Tan Bernhard Bettler Binding of HCN channels to GABAB receptors in dopamine neurons of the VTA limits synaptic inhibition and prevents the development of anxiety Neurobiology of Disease GABA-A GABA-B HCN2 Hyperpolarization-activated cyclic nucleotide-gated channels Late IPSP Slow IPSP |
| title | Binding of HCN channels to GABAB receptors in dopamine neurons of the VTA limits synaptic inhibition and prevents the development of anxiety |
| title_full | Binding of HCN channels to GABAB receptors in dopamine neurons of the VTA limits synaptic inhibition and prevents the development of anxiety |
| title_fullStr | Binding of HCN channels to GABAB receptors in dopamine neurons of the VTA limits synaptic inhibition and prevents the development of anxiety |
| title_full_unstemmed | Binding of HCN channels to GABAB receptors in dopamine neurons of the VTA limits synaptic inhibition and prevents the development of anxiety |
| title_short | Binding of HCN channels to GABAB receptors in dopamine neurons of the VTA limits synaptic inhibition and prevents the development of anxiety |
| title_sort | binding of hcn channels to gabab receptors in dopamine neurons of the vta limits synaptic inhibition and prevents the development of anxiety |
| topic | GABA-A GABA-B HCN2 Hyperpolarization-activated cyclic nucleotide-gated channels Late IPSP Slow IPSP |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000476 |
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