Abstract
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.
Highlights
The medial habenula (MHb) is an epithalamic structure that exclusively projects to the interpeduncular nucleus (IPN), with the dorsal MHb projecting to the lateral IPN and the ventral MHb projecting to the rostral and central subnuclei of the IPN (Figure 1A)
We confirmed that rostral IPN neurons exhibit a strong increase in excitatory postsynaptic current (EPSC) amplitudes following GABAB receptor (GBR) activation with 1 mM baclofen (Figure 1C), whereas EPSC amplitudes were reduced by baclofen in lateral IPN neurons (Figure 1D)
GABAB1, KCTD8, and KCTD12 showed peak localization in the peri-synaptic region with lower particle densities inside the active zone (Figure 3B–D). These results suggest that KCTD12b prominently localized to the active zone of ventral MHb terminals in the rostral IPN, whereas KCTD8 dominates the active zone of dorsal MHb terminals in the lateral IPN (Figure 3F)
Summary
The medial habenula (MHb) is an epithalamic structure that exclusively projects to the interpeduncular nucleus (IPN), with the dorsal MHb projecting to the lateral IPN and the ventral MHb projecting to the rostral and central subnuclei of the IPN (Figure 1A). Activation of presynaptic GABAB receptors (GBRs) on MHb terminals exerts an unusual facilitatory effect by increasing neurotransmitter release up to 10-fold (Zhang et al, 2016), and this effect appears to be involved in synaptic plasticity (Koppensteiner et al, 2017). Cav2.3 currents were enhanced by co-expression of KCTD8, but not KCTD12b in the absence of GBRs. Strikingly, genetic deletion of KCTD8 or KCTD12b reduced or increased, respectively, the probability of neurotransmitter release in the ventral MHb to the rostral IPN pathway without affecting GBR-mediated potentiation. Viral expression of KCTD12b in MHb neurons reduced the increased release probability in KCTD12b KO mice, whereas overexpression of KCTD8 in MHb neurons of wild-type mice increased release probability These results support that synaptic strength at the MHb-IPN pathway is scaled via GBR-independent Cav2.3–KCTD interactions in the presynaptic active zone
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