The Excitatory Effects of GABA Within the Suprachiasmatic Nucleus: Regulation of Na-K-2Cl Cotransporters (NKCCs) by Environmental Lighting Conditions

Overview

Journal J Biol Rhythms

Date 2020 May 15

PMID 32406304

Citations 5

Authors

John K McNeill 4th

James C Walton

Vitaly Ryu

H Elliott Albers

Affiliations

Soon will be listed here.

Abstract

The suprachiasmatic nucleus (SCN) contains a pacemaker that generates circadian rhythms and entrains them with the 24-h light-dark cycle (LD). The SCN is composed of 16,000 to 20,000 heterogeneous neurons in bilaterally paired nuclei. γ-amino butyric acid (GABA) is the primary neurochemical signal within the SCN and plays a key role in regulating circadian function. While GABA is the primary inhibitory neurotransmitter in the brain, there is now evidence that GABA can also exert excitatory effects in the adult brain. Cation chloride cotransporters determine the effects of GABA on chloride equilibrium, thereby determining whether GABA produces hyperpolarizing or depolarizing actions following activation of GABA receptors. The activity of Na-K-2Cl cotransporter1 (NKCC1), the most prevalent chloride influx cotransporter isoform in the brain, plays a critical role in determining whether GABA has depolarizing effects. In the present study, we tested the hypothesis that NKCC1 protein expression in the SCN is regulated by environmental lighting and displays daily and circadian changes in the intact circadian system of the Syrian hamster. In hamsters housed in constant light (LL), the overall NKCC1 immunoreactivity (NKCC1-ir) in the SCN was significantly greater than in hamsters housed in LD or constant darkness (DD), although NKCC1 protein levels in the SCN were not different between hamsters housed in LD and DD. In hamsters housed in LD cycles, no differences in NKCC1-ir within the SCN were observed over the 24-h cycle. NKCC1 protein in the SCN was found to vary significantly over the circadian cycle in hamsters housed in free-running conditions. Overall, NKCC1 protein was greater in the ventral SCN than in the dorsal SCN, although no significant differences were observed across lighting conditions or time of day in either subregion. These data support the hypothesis that NKCC1 protein expression can be regulated by environmental lighting and circadian mechanisms within the SCN.

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References

Liu C, Reppert S . GABA synchronizes clock cells within the suprachiasmatic circadian clock. Neuron. 2000; 25(1):123-8. DOI: 10.1016/s0896-6273(00)80876-4. View

Clayton G, Owens G, Wolff J, Smith R . Ontogeny of cation-Cl- cotransporter expression in rat neocortex. Brain Res Dev Brain Res. 1998; 109(2):281-92. DOI: 10.1016/s0165-3806(98)00078-9. View

Vuillez P, Jacob N, Pevet P . In Syrian and European hamsters, the duration of sensitive phase to light of the suprachiasmatic nuclei depends on the photoperiod. Neurosci Lett. 1996; 208(1):37-40. DOI: 10.1016/0304-3940(96)12535-0. View

Myung J, Hong S, Hatanaka F, Nakajima Y, De Schutter E, Takumi T . Period coding of Bmal1 oscillators in the suprachiasmatic nucleus. J Neurosci. 2012; 32(26):8900-18. PMC: 6622328. DOI: 10.1523/JNEUROSCI.5586-11.2012. View

Klett N, Allen C . Intracellular Chloride Regulation in AVP+ and VIP+ Neurons of the Suprachiasmatic Nucleus. Sci Rep. 2017; 7(1):10226. PMC: 5579040. DOI: 10.1038/s41598-017-09778-x. View

Moore R, Speh J . GABA is the principal neurotransmitter of the circadian system. Neurosci Lett. 1993; 150(1):112-6. DOI: 10.1016/0304-3940(93)90120-a. View

Farajnia S, van Westering T, Meijer J, Michel S . Seasonal induction of GABAergic excitation in the central mammalian clock. Proc Natl Acad Sci U S A. 2014; 111(26):9627-32. PMC: 4084452. DOI: 10.1073/pnas.1319820111. View

Freeman Jr G, Krock R, Aton S, Thaben P, Herzog E . GABA networks destabilize genetic oscillations in the circadian pacemaker. Neuron. 2013; 78(5):799-806. PMC: 3683151. DOI: 10.1016/j.neuron.2013.04.003. View

DeWoskin D, Myung J, Belle M, Piggins H, Takumi T, Forger D . Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping. Proc Natl Acad Sci U S A. 2015; 112(29):E3911-9. PMC: 4517259. DOI: 10.1073/pnas.1420753112. View

10.

Stephan F, Zucker I . Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci U S A. 1972; 69(6):1583-6. PMC: 426753. DOI: 10.1073/pnas.69.6.1583. View

11.

Gribkoff V, Pieschl R, Wisialowski T, Park W, Strecker G, de Jeu M . A reexamination of the role of GABA in the mammalian suprachiasmatic nucleus. J Biol Rhythms. 1999; 14(2):126-30. DOI: 10.1177/074873099129000515. View

12.

Taylor S, Wang T, Granados-Fuentes D, Herzog E . Resynchronization Dynamics Reveal that the Ventral Entrains the Dorsal Suprachiasmatic Nucleus. J Biol Rhythms. 2017; 32(1):35-47. PMC: 5483321. DOI: 10.1177/0748730416680904. View

13.

Belenky M, Sollars P, Mount D, Alper S, Yarom Y, Pickard G . Cell-type specific distribution of chloride transporters in the rat suprachiasmatic nucleus. Neuroscience. 2009; 165(4):1519-37. PMC: 2815043. DOI: 10.1016/j.neuroscience.2009.11.040. View

14.

Ralph M, Menaker M . Bicuculline blocks circadian phase delays but not advances. Brain Res. 1985; 325(1-2):362-5. DOI: 10.1016/0006-8993(85)90341-5. View

15.

Alamilla J, Perez-Burgos A, Quinto D, Aguilar-Roblero R . Circadian modulation of the Cl(-) equilibrium potential in the rat suprachiasmatic nuclei. Biomed Res Int. 2014; 2014:424982. PMC: 4052495. DOI: 10.1155/2014/424982. View

16.

Wagner S, Sagiv N, Yarom Y . GABA-induced current and circadian regulation of chloride in neurones of the rat suprachiasmatic nucleus. J Physiol. 2001; 537(Pt 3):853-69. PMC: 2279012. DOI: 10.1111/j.1469-7793.2001.00853.x. View

17.

Aton S, Huettner J, Straume M, Herzog E . GABA and Gi/o differentially control circadian rhythms and synchrony in clock neurons. Proc Natl Acad Sci U S A. 2006; 103(50):19188-93. PMC: 1748197. DOI: 10.1073/pnas.0607466103. View

18.

Yan L, Karatsoreos I, LeSauter J, Welsh D, Kay S, Foley D . Exploring spatiotemporal organization of SCN circuits. Cold Spring Harb Symp Quant Biol. 2008; 72:527-41. PMC: 3281753. DOI: 10.1101/sqb.2007.72.037. View

19.

Challet E, Denis I, Rochet V, Aioun J, Gourmelen S, Lacroix H . The role of PPARβ/δ in the regulation of glutamatergic signaling in the hamster suprachiasmatic nucleus. Cell Mol Life Sci. 2012; 70(11):2003-14. PMC: 11113465. DOI: 10.1007/s00018-012-1241-9. View

20.

Okamura H, Berod A, Julien J, Geffard M, Kitahama K, Mallet J . Demonstration of GABAergic cell bodies in the suprachiasmatic nucleus: in situ hybridization of glutamic acid decarboxylase (GAD) mRNA and immunocytochemistry of GAD and GABA. Neurosci Lett. 1989; 102(2-3):131-6. DOI: 10.1016/0304-3940(89)90067-0. View