Balancing Tonic and Phasic Inhibition in Hypothalamic Corticotropin-releasing Hormone Neurons

Overview

Journal J Physiol

Specialty Physiology

Date 2018 Feb 9

PMID 29419884

Citations 18

Authors

Phillip L W Colmers

Jaideep S Bains

Affiliations

Soon will be listed here.

Abstract

Key Points: GABA transporter (GAT) blockade recruits extrasynaptic GABA receptors (GABA Rs) and amplifies constitutive presynaptic GABA R activity. Extrasynaptic GABA Rs contribute to a tonic current. Corticosteroids increase the tonic current mediated by extrasynaptic GABA Rs.

Abstract: Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are integratory hubs that regulate the endocrine response to stress. GABA inputs provide a basal inhibitory tone that constrains this system and circulating glucocorticoids (CORT) are important feedback controllers of CRH output. Surprisingly little is known about the direct effects of CORT on GABA synapses in PVN. Here we used whole-cell patch clamp recordings from CRH neurons in mouse hypothalamic brain slices to examine the effects of CORT on synaptic and extrasynaptic GABA signalling. We show that GABA transporters (GATs) limit constitutive activation of presynaptic GABA receptors and ensure high release probability at GABA synapses. GATs in combination with GABA receptors also curtail extrasynaptic GABA R signalling. CORT has no effect on synaptic GABA signalling, but increases extrasynaptic GABA tone through upregulation of postsynaptic GABA receptors. These data show that efficient GABA clearance and autoinhibition control the balance between synaptic (phasic) and extrasynaptic (tonic) inhibition in PVN CRH neurons. This balance is shifted towards increased extrasynaptic inhibition by CORT.

Citing Articles

Efficacy and safety of auricular acupressure on reduction of estazolam in patients with insomnia: a study protocol for a three-arm, blinded randomized controlled trial.

Wu Q, Wang J, Fan L, Qian L, Han D, Hu H BMC Complement Med Ther. 2024; 24(1):367.

PMID: 39395964 PMC: 11471019. DOI: 10.1186/s12906-024-04651-7.

Sustained Inhibition of GABA-AT by OV329 Enhances Neuronal Inhibition and Prevents Development of Benzodiazepine Refractory Seizures.

Colmers P, Arshad M, Mukherjee J, Lin S, Ng S, Sarmiere P eNeuro. 2024; 11(7).

PMID: 38937107 PMC: 11236575. DOI: 10.1523/ENEURO.0137-24.2024.

Early establishment of chloride homeostasis in CRH neurons is altered by prenatal stress leading to fetal HPA axis dysregulation.

Watanabe M, Sinha A, Shinmyo Y, Fukuda A Front Mol Neurosci. 2024; 17:1373337.

PMID: 38577026 PMC: 10994000. DOI: 10.3389/fnmol.2024.1373337.

Radix Water Extract Alleviate Type 2 Diabetes Mellitus in db/db Mice through Comprehensive Regulation of Metabolism and Gut Microbiota.

Li J, Zhang H, Ouyang H, Xu W, Sun Y, Zhong Y Molecules. 2023; 28(22).

PMID: 38005193 PMC: 10673130. DOI: 10.3390/molecules28227471.

Influence of Mild Chronic Stress and Social Isolation on Acute Ozone-Induced Alterations in Stress Biomarkers and Brain-Region-Specific Gene Expression in Male Wistar-Kyoto Rats.

Valdez M, Freeborn D, Valdez J, Henriquez A, J Snow S, Jackson T Antioxidants (Basel). 2023; 12(11).

PMID: 38001817 PMC: 10669107. DOI: 10.3390/antiox12111964.

References

Kittler J, Moss S . Modulation of GABAA receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic inhibition. Curr Opin Neurobiol. 2003; 13(3):341-7. DOI: 10.1016/s0959-4388(03)00064-3. View

Ye P, Kenyon C, MacKenzie S, Nichol K, Seckl J, Fraser R . Effects of ACTH, dexamethasone, and adrenalectomy on 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) gene expression in the rat central nervous system. J Endocrinol. 2008; 196(2):305-11. PMC: 2229629. DOI: 10.1677/JOE-07-0439. View

Park J, Skalska S, Stern J . Characterization of a novel tonic gamma-aminobutyric acidA receptor-mediated inhibition in magnocellular neurosecretory neurons and its modulation by glia. Endocrinology. 2006; 147(8):3746-60. DOI: 10.1210/en.2006-0218. View

Mitrovic I, Riley R, Jan L, Basbaum A . Immunohistochemical localization of GABA(B) receptors in the rat central nervous system. J Comp Neurol. 1999; 405(3):299-321. DOI: 10.1002/(sici)1096-9861(19990315)405:3<299::aid-cne2>3.0.co;2-6. View

Bianchi M, Lux-Lantos V, Bettler B, Libertun C . Expression of gamma-aminobutyric acid B receptor subunits in hypothalamus of male and female developing rats. Brain Res Dev Brain Res. 2005; 160(2):124-9. DOI: 10.1016/j.devbrainres.2005.06.017. View

Lee V, MacKenzie G, Hooper A, Maguire J . Reduced tonic inhibition in the dentate gyrus contributes to chronic stress-induced impairments in learning and memory. Hippocampus. 2016; 26(10):1276-1290. PMC: 5030140. DOI: 10.1002/hipo.22604. View

Taniguchi H, He M, Wu P, Kim S, Paik R, Sugino K . A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron. 2011; 71(6):995-1013. PMC: 3779648. DOI: 10.1016/j.neuron.2011.07.026. View

Agis-Balboa R, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E . Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc Natl Acad Sci U S A. 2006; 103(39):14602-7. PMC: 1600006. DOI: 10.1073/pnas.0606544103. View

Cullinan W, Helmreich D, Watson S . Fos expression in forebrain afferents to the hypothalamic paraventricular nucleus following swim stress. J Comp Neurol. 1996; 368(1):88-99. DOI: 10.1002/(SICI)1096-9861(19960422)368:1<88::AID-CNE6>3.0.CO;2-G. View

10.

Di S, Malcher-Lopes R, Halmos K, Tasker J . Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci. 2003; 23(12):4850-7. PMC: 6741208. View

11.

Park J, Jo J, Zheng H, Patel K, Stern J . Regulation of tonic GABA inhibitory function, presympathetic neuronal activity and sympathetic outflow from the paraventricular nucleus by astroglial GABA transporters. J Physiol. 2009; 587(Pt 19):4645-60. PMC: 2768019. DOI: 10.1113/jphysiol.2009.173435. View

12.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View

13.

Wamsteeker Cusulin J, Fuzesi T, Inoue W, Bains J . Glucocorticoid feedback uncovers retrograde opioid signaling at hypothalamic synapses. Nat Neurosci. 2013; 16(5):596-604. PMC: 4844536. DOI: 10.1038/nn.3374. View

14.

Farrant M, Nusser Z . Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci. 2005; 6(3):215-29. DOI: 10.1038/nrn1625. View

15.

Miklos I, Kovacs K . Reorganization of synaptic inputs to the hypothalamic paraventricular nucleus during chronic psychogenic stress in rats. Biol Psychiatry. 2011; 71(4):301-8. DOI: 10.1016/j.biopsych.2011.10.027. View

16.

Reddy D, Rogawski M . Stress-induced deoxycorticosterone-derived neurosteroids modulate GABA(A) receptor function and seizure susceptibility. J Neurosci. 2002; 22(9):3795-805. PMC: 6758375. DOI: 20026274. View

17.

Biag J, Huang Y, Gou L, Hintiryan H, Askarinam A, Hahn J . Cyto- and chemoarchitecture of the hypothalamic paraventricular nucleus in the C57BL/6J male mouse: a study of immunostaining and multiple fluorescent tract tracing. J Comp Neurol. 2011; 520(1):6-33. PMC: 4104804. DOI: 10.1002/cne.22698. View

18.

Orchinik M, Weiland N, McEwen B . Chronic exposure to stress levels of corticosterone alters GABAA receptor subunit mRNA levels in rat hippocampus. Brain Res Mol Brain Res. 1995; 34(1):29-37. DOI: 10.1016/0169-328x(95)00118-c. View

19.

Rossi D, Hamann M . Spillover-mediated transmission at inhibitory synapses promoted by high affinity alpha6 subunit GABA(A) receptors and glomerular geometry. Neuron. 1998; 20(4):783-95. DOI: 10.1016/s0896-6273(00)81016-8. View

20.

Liu X, Tribollet E, Raggenbass M . GABA(B) receptor-activation inhibits GABAergic synaptic transmission in parvocellular neurones of rat hypothalamic paraventricular nucleus. J Neuroendocrinol. 2006; 18(3):177-86. DOI: 10.1111/j.1365-2826.2005.01402.x. View