@phdthesis{19271, abstract = {The medial habenula (MHb) is implicated in regulating emotional responses to aversive events. Studies in zebrafish have identified a remarkable morphological left-right asymmetry in the dorsal habenula (zebrafish equivalent of mammalian MHb)-to-interpeduncular nucleus (IPN) pathway and its left-side specific role in modulating fear responses. However, there is little evidence for structural or functional lateralization in the mammalian MHb-IPN pathway. Here, I investigated the synaptic properties of the left and right MHb afferents to the IPN in mice and addressed whether these synaptic connections selectively influence the expression of conditioned fear in mice. My findings reveal that each individual IPN neuron receives inputs from both left and right MHb. Electrophysiological recordings from the same postsynaptic IPN neurons demonstrate that the left MHb-originating synapses exhibit lower release probability and higher 𝛾-aminobutyric acid type B receptor (GABABR)-mediated potentiation compared to the right MHb-originating synapses. Interestingly, chemogenetic inhibition of cholinergic neurons in the left but not the right MHb significantly attenuated cue-dependent fear recall. Furthermore, conditional deletion of GABABR in the left MHb interfered with the recall of cued fear memory, whereas that in the right MHb neurons spared fear memory expression. Collectively, I demonstrate a functional asymmetry of the MHb in mice, revealing a predominant role for GABABR-mediated signaling in the left MHb-IPN pathway in the modulation of fear memories. These findings suggest that lateralized pathways could represent a fundamental principle in the neural regulation of emotion across species.}, author = {Önal, Hüseyin C}, issn = {2663-337X}, publisher = {Institute of Science and Technology Austria}, title = {{Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula}}, doi = {10.15479/AT-ISTA-19271}, year = {2025}, } @article{15084, abstract = {GABAB receptor (GBR) activation inhibits neurotransmitter release in axon terminals in the brain, except in medial habenula (MHb) terminals, which show robust potentiation. However, mechanisms underlying this enigmatic potentiation remain elusive. Here, we report that GBR activation on MHb terminals induces an activity-dependent transition from a facilitating, tonic to a depressing, phasic neurotransmitter release mode. This transition is accompanied by a 4.1-fold increase in readily releasable vesicle pool (RRP) size and a 3.5-fold increase of docked synaptic vesicles (SVs) at the presynaptic active zone (AZ). Strikingly, the depressing phasic release exhibits looser coupling distance than the tonic release. Furthermore, the tonic and phasic release are selectively affected by deletion of synaptoporin (SPO) and Ca 2+ -dependent activator protein for secretion 2 (CAPS2), respectively. SPO modulates augmentation, the short-term plasticity associated with tonic release, and CAPS2 retains the increased RRP for initial responses in phasic response trains. The cytosolic protein CAPS2 showed a SV-associated distribution similar to the vesicular transmembrane protein SPO, and they were colocalized in the same terminals. We developed the “Flash and Freeze-fracture” method, and revealed the release of SPO-associated vesicles in both tonic and phasic modes and activity-dependent recruitment of CAPS2 to the AZ during phasic release, which lasted several minutes. Overall, these results indicate that GBR activation translocates CAPS2 to the AZ along with the fusion of CAPS2-associated SVs, contributing to persistency of the RRP increase. Thus, we identified structural and molecular mechanisms underlying tonic and phasic neurotransmitter release and their transition by GBR activation in MHb terminals.}, author = {Koppensteiner, Peter and Bhandari, Pradeep and Önal, Hüseyin C and Borges Merjane, Carolina and Le Monnier, Elodie and Roy, Utsa and Nakamura, Yukihiro and Sadakata, Tetsushi and Sanbo, Makoto and Hirabayashi, Masumi and Rhee, JeongSeop and Brose, Nils and Jonas, Peter M and Shigemoto, Ryuichi}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {8}, publisher = {National Academy of Sciences}, title = {{GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles}}, doi = {10.1073/pnas.2301449121}, volume = {121}, year = {2024}, } @article{9437, 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.}, author = {Bhandari, Pradeep and Vandael, David H and Fernández-Fernández, Diego and Fritzius, Thorsten and Kleindienst, David and Önal, Hüseyin C and Montanaro-Punzengruber, Jacqueline-Claire and Gassmann, Martin and Jonas, Peter M and Kulik, Akos and Bettler, Bernhard and Shigemoto, Ryuichi and Koppensteiner, Peter}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals}}, doi = {10.7554/ELIFE.68274}, volume = {10}, year = {2021}, }