Thomas M. Morse,
Chiayu Q. Chiu,
Francesca Nani,
Frederic Knoflach,
Maria-Clemencia Hernandez,
Monika Jadi,
Michael J. HigleyZoom link for the meeting:
https://yale.zoom.us/j/95416954987(A video teaser TonicInhib2.mov, and the poster TonicInhibition.pdf are now available below)
Brain activity is highly regulated by GABAergic activity, which acts via GABAARs to suppress somatic spike generation as well as dendritic synaptic integration and calcium signaling. Tonic GABAergic conductances mediated by distinct receptor subtypes can also inhibit neuronal excitability and spike output, though the consequences for dendritic calcium signaling are unclear. Here, we use 2-photon calcium imaging in cortical pyramidal neurons and computational modeling to show that low affinity GABAARs containing an alpha5 subunit mediate a tonic hyperpolarization of the dendritic membrane potential, resulting in deinactivation of voltage-gated calcium channels and a paradoxical boosting of action potential-evoked calcium influx. We also find that GABAergic enhancement of calcium signaling modulates short-term synaptic plasticity, augmenting depolarization-induced suppression of inhibition. These results demonstrate a novel role for GABA in the control of dendritic activity and suggest a mechanism for differential modulation of electrical and biochemical signaling.
Acknowledgements: The authors wish to thank members of the Higley laboratory and Dr. Jessica A. Cardin for helpful comments, the Yale Center for Research Computing for support with the Yale Farnam high performance cluster, Henner Knust for compound synthesis, Chiristian Miscenic and Marcello Foggetta for cell transfections and membrane preparations, Judith Lengyel, Gregoire Friz, and Maria Karg for cell line generation and radioligand binding assays, and Marie Claire Pflimlin for support with electrophysiological characterization of Compound A selectivity. This work was supported by funding from the NIH/NIMH (R01 MH099045 and MD113852 to MJH, K01 MH097961 to CQC), funding agencies in Chile (FONDECYT No. 1171840 and MILENIO PROYECTO P09-022-F, CINV to CQC), and Roche Pharmaceutical.
