The synaptic connection from medial habenula (MHb) to interpeduncular nucleus (IPN) is critical for emotion-related behaviors, and uniquely expresses R-type Ca2+ channels (Cav2.3) and auxiliary GABAB receptor (GBR) subunits, the K+-channel tetramerization domain-containing proteins (KCTDs). Activation of GBRs facilitates or inhibits transmitter release from MHb terminals depending on the IPN subnucleus, but the role of KCTDs is unknown. We therefore examined the localization and function of Cav2.3, GBRs, and KCTDs in this pathway in mice. We show in heterologous cells that KCTD8 and KCTD12b directly bind to Cav2.3 and that KCTD8 potentiates Cav2.3 currents in the absence of GBRs. In the rostral IPN, KCTD8, KCTD12b and Cav2.3 co-localize at the presynaptic active zone. Genetic deletion indicated a bidirectional modulation of Cav2.3-mediated release by these KCTDs with a compensatory increase of KCTD8 in the active zone in KCTD12b-deficient mice. The interaction of Cav2.3 with KCTDs therefore scales synaptic strength independent of GBR activation.
For all figures, numerical data that are represented in graphs are provided as source data excel files.
- Ryuichi Shigemoto
- Peter Jonas
- Bernhard Bettler
- Cihan Önal
- Akos Kulik
- Akos Kulik
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All experiments were performed in accordance with the license approved by the Austrian Federal Ministry of Science and Research (Animal license number: BMWFW-66.018/0012-WF/V/3b/2016) and the Austrian and EU animal laws.
- Yukiko Goda, RIKEN, Japan
- Received: March 10, 2021
- Accepted: April 28, 2021
- Accepted Manuscript published: April 29, 2021 (version 1)
© 2021, Bhandari et al.
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