Estradiol modulates the efficacy of synaptic inhibition by decreasing the dwell time of GABAA receptors at inhibitory synapses
Edited by Richard L. Huganir, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved September 22, 2017 (received for review March 28, 2017)
Significance
Our knowledge of how estrogen signaling can influence inhibitory synaptic transmission is rudimentary and is addressed here. Collectively, our data suggest that estrogen modulates the dynamics of surface GABAA receptors and hence efficacy of synaptic inhibition, via a postsynaptic mechanism that relies on disrupting the postsynaptic scaffold. This regulatory mechanism may have profound effects on the efficacy of neuronal inhibition and therefore synaptic plasticity and thus play a role in the pathophysiology of estrogen-related seizure and cognitive disorders.
Abstract
Estrogen plays a critical role in many physiological processes and exerts profound effects on behavior by regulating neuronal excitability. While estrogen has been established to exert effects on dendritic morphology and excitatory neurotransmission its role in regulating neuronal inhibition is poorly understood. Fast synaptic inhibition in the adult brain is mediated by specialized populations of γ-c aA receptors (GABAARs) that are selectively enriched at synapses, a process dependent upon their interaction with the inhibitory scaffold protein gephyrin. Here we have assessed the role that estradiol (E2) plays in regulating the dynamics of GABAARs and stability of inhibitory synapses. Treatment of cultured cortical neurons with E2 reduced the accumulation of GABAARs and gephyrin at inhibitory synapses. However, E2 exposure did not modify the expression of either the total or the plasma membrane GABAARs or gephyrin. Mechanistically, single-particle tracking revealed that E2 treatment selectively reduced the dwell time and thereby decreased the confinement of GABAARs at inhibitory synapses. Consistent with our cell biology measurements, we observed a significant reduction in amplitude of inhibitory synaptic currents in both cultured neurons and hippocampal slices exposed to E2, while their frequency was unaffected. Collectively, our results suggest that acute exposure of neurons to E2 leads to destabilization of GABAARs and gephyrin at inhibitory synapses, leading to reductions in the efficacy of GABAergic inhibition via a postsynaptic mechanism.
Acknowledgments
This work was supported by funding from AstraZeneca, and NIH Grants NS051195, NS081986, MH097446, DA037170-01, 1R01NS087662, MH106954 and Department of Defense Grant AR140209 (to S.J.M.) and NIH, National Institute of Neurological Disorders and Stroke Grant R01 NS073574 (to J. Maguire). S.J.M. acknowledges the support of Grant P30 NS047243 that supports the Tufts Center for Neuroscience Research. A.T. is supported by the Agence Nationale de la Recherche “Synaptune” (Programme blanc, ANR-12-BSV4-0019-01), European Research Council advanced research grant “PlasltInhib”, the program “Investissements d’Avenir” (ANR-10-LABX-54 MEMO LIFE and ANR-11-IDEX-0001-02 PSL* Research University), and the Institut National de la Santé et de la Recherche Médicale). D.P.S. is supported by Medical Research Council Grant MR/L021064/1.
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Cover image: Pictured is a developing Arabidopsis thaliana lateral root labeled with a fluorescent transcriptional reporter, with cell outlines shown in blue. Yujuan Du and Ben Scheres found that the PLETHORA transcription factors PLT3, PLT5, and PLT7 regulate the initiation of cell divisions at the start of Arabidopsis lateral root development. According to the authors, PLETHORA transcription factors are key molecular triggers for the establishment of new meristems and tissue differentiation associated with a new growth axis. See the article by Yujuan Du and Ben Scheres on pages 11709–11714. Image courtesy of Yujuan Du.
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© 2017. Published under the PNAS license.
Submission history
Published online: October 16, 2017
Published in issue: October 31, 2017
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Acknowledgments
This work was supported by funding from AstraZeneca, and NIH Grants NS051195, NS081986, MH097446, DA037170-01, 1R01NS087662, MH106954 and Department of Defense Grant AR140209 (to S.J.M.) and NIH, National Institute of Neurological Disorders and Stroke Grant R01 NS073574 (to J. Maguire). S.J.M. acknowledges the support of Grant P30 NS047243 that supports the Tufts Center for Neuroscience Research. A.T. is supported by the Agence Nationale de la Recherche “Synaptune” (Programme blanc, ANR-12-BSV4-0019-01), European Research Council advanced research grant “PlasltInhib”, the program “Investissements d’Avenir” (ANR-10-LABX-54 MEMO LIFE and ANR-11-IDEX-0001-02 PSL* Research University), and the Institut National de la Santé et de la Recherche Médicale). D.P.S. is supported by Medical Research Council Grant MR/L021064/1.
Notes
This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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