Cholecystokinin-expressing interneurons (CCK-INs) mediate behavior state-dependent inhibition in cortical circuits and themselves receive strong GABAergic input. However, it remains unclear to what extent GABABreceptors (GABABRs) contribute to their inhibitory control. Using immunoelectron microscopy, we found that CCK-INs in the rat hippocampus possessed high levels of dendritic GABABRs and KCTD12 auxiliary proteins, whereas postsynaptic effector Kir3 channels were present at lower levels. Consistently, whole-cell recordings revealed slow GABABR-mediated inhibitory postsynaptic currents (IPSCs) in most CCK-INs. In spite of the higher surface density of GABABRs in CCK-INs than in CA1 principal cells, the amplitudes of IPSCs were comparable, suggesting that the expression of Kir3 channels is the limiting factor for the GABABR currents in these INs. Morphological analysis showed that CCK-INs were diverse, comprising perisomatic-targeting basket cells (BCs), as well as dendrite-targeting (DT) interneurons, including a previously undescribed DT type. GABABR-mediated IPSCs in CCK-INs were large in BCs, but small in DT subtypes. In response to prolonged activation, GABABR-mediated currents displayed strong desensitization, which was absent in KCTD12-deficient mice. This study highlights that GABABRs differentially control CCK-IN subtypes, and the kinetics and desensitization of GABABR-mediated currents are modulated by KCTD12 proteins.
This work was supported by the Deutsche Forschungsgemeinschaft (DFG SFB 780 A2, A.K.; SFB TR3 I.V. and EXC 257, I.V.; FOR 2143, A.K. and I.V.), Spemann Graduate School (D.A.), BIOSS-2 (A6, A.K.), the Swiss National Science Foundation (3100A0-117816, B.B.), The McNaught Bequest (S.A.B. and I.V.), and Tenovus Scotland (I.V.). We thank Cheryl Hutton and Chinmaya Sadangi for their contributions to neuronal reconstruction as well as Natalie Wernet, Sigrun Nestel, Anikó Schneider, Ina Wolter, and Ulrich Noeller for their excellent technical support. VGAT-Venus transgenic rats were generated by Drs Y. Yanagawa, M. Hirabayashi, and Y. Kawaguchi in National Institute for Physiological Sciences, Okazaki, Japan, using pCS2-Venus provided by Dr A. Miyawaki. The monoclonal mouse CCK antibody was generously provided by Dr G.V. Ohning, CURE Center, UCLA, CA.
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Booker S, Althof D, Gross A, et al. KCTD12 auxiliary proteins modulate kinetics of GABAB receptor-mediated inhibition in Cholecystokinin-containing interneurons. Cerebral Cortex. 2016;27(3):2318-2334. doi:10.1093/cercor/bhw090
Booker, S., Althof, D., Gross, A., Loreth, D., Müller, J., Unger, A., … Kulik, Á. (2016). KCTD12 auxiliary proteins modulate kinetics of GABAB receptor-mediated inhibition in Cholecystokinin-containing interneurons. Cerebral Cortex, 27(3), 2318–2334. https://doi.org/10.1093/cercor/bhw090
Booker, Sam, Daniel Althof, Anna Gross, Desiree Loreth, Johanna Müller, Andreas Unger, Bernd Fakler, et al. “KCTD12 Auxiliary Proteins Modulate Kinetics of GABAB Receptor-Mediated Inhibition in Cholecystokinin-Containing Interneurons.” Cerebral Cortex 27, no. 3 (2016): 2318–34. https://doi.org/10.1093/cercor/bhw090.
S. Booker et al., “KCTD12 auxiliary proteins modulate kinetics of GABAB receptor-mediated inhibition in Cholecystokinin-containing interneurons,” Cerebral Cortex, vol. 27, no. 3, pp. 2318–2334, 2016.
Booker S, Althof D, Gross A, Loreth D, Müller J, Unger A, Fakler B, Varro A, Watanabe M, Gassmann M, Bettler B, Shigemoto R, Vida I, Kulik Á. 2016. KCTD12 auxiliary proteins modulate kinetics of GABAB receptor-mediated inhibition in Cholecystokinin-containing interneurons. Cerebral Cortex. 27(3), 2318–2334.
Booker, Sam, et al. “KCTD12 Auxiliary Proteins Modulate Kinetics of GABAB Receptor-Mediated Inhibition in Cholecystokinin-Containing Interneurons.” Cerebral Cortex, vol. 27, no. 3, Oxford University Press, 2016, pp. 2318–34, doi:10.1093/cercor/bhw090.