Changes in circadian period and morphology of the hypothalamic suprachiasmatic nucleus in fyn kinase-deficient mice

GABA is a principal neurotransmitter in the hypothalamic suprachiasmatic nucleus (SCN) that contributes to intercellular communication between individual circadian oscillators within the SCN network and the stability and precision of the circadian rhythms. GABA transporters (GAT) regulate the extracellular GABA concentration and modulate GABAA receptor (GABAAR)-mediated currents. GABA transport inhibitors were applied to study how GABAAR-mediated currents depend on the expression and function of GAT. Nipecotic acid inhibits GABA transport and induced an inward tonic current in concentration-dependent manner during whole cell patch-clamp recordings from SCN neurons. Application of either the selective GABA transporter 1 (GAT1) inhibitors NNC-711 or SKF-89976A, or the GABA transporter 3 (GAT3) inhibitor SNAP-5114, produced only small changes of the baseline current. Coapplication of GAT1 and GAT3 inhibitors induced a significant GABAAR-mediated tonic current that was blocked by gabazine. GAT inhibitors decreased the amplitude and decay time constant and increased the rise time of spontaneous GABAAR-mediated postsynaptic currents. However, inhibition of GAT did not alter the expression of either GAT1 or GAT3 in the hypothalamus. Thus GAT1 and GAT3 functionally complement each other to regulate the extracellular GABA concentration and GABAAR-mediated synaptic and tonic currents in the SCN. Coapplication of SKF-89976A and SNAP-5114 (50 µM each) significantly reduced the circadian period of Per1 expression in the SCN by 1.4 h. Our studies demonstrate that GAT are important regulators of GABAAR-mediated currents and the circadian clock in the SCN. NEW & NOTEWORTHY In the suprachiasmatic nucleus (SCN), the GABA transporters GAT1 and GAT3 are expressed in astrocytes. Inhibition of these GABA transporters increased a tonic GABA current and reduced the circadian period of Per1 expression in SCN neurons. GAT1 and GAT3 showed functional cooperativity: inhibition of one GAT increased the activity but not the expression of the other. Our data demonstrate that GABA transporters are important regulators of GABAA receptor-mediated currents and the circadian clock.

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Astrocytic Modulation of Neuronal Activity in the Suprachiasmatic Nucleus: Insights from Mathematical Modeling

Journal of Biological Rhythms ◽

10.1177/0748730420913672 ◽

2020 ◽

Vol 35 (3) ◽

pp. 287-301

Author(s):

Natthapong Sueviriyapan ◽

Chak Foon Tso ◽

Erik D. Herzog ◽

Michael A. Henson

Keyword(s):

Circadian Rhythm ◽

Suprachiasmatic Nucleus ◽

Neuronal Activity ◽

Clock Genes ◽

Rhythmic Activity ◽

Neuronal Population ◽

Circadian Period ◽

Circadian Oscillators ◽

Bidirectional Interactions ◽

The Impact

The suprachiasmatic nucleus (SCN) of the hypothalamus consists of a highly heterogeneous neuronal population networked together to allow precise and robust circadian timekeeping in mammals. While the critical importance of SCN neurons in regulating circadian rhythms has been extensively studied, the roles of SCN astrocytes in circadian system function are not well understood. Recent experiments have demonstrated that SCN astrocytes are circadian oscillators with the same functional clock genes as SCN neurons. Astrocytes generate rhythmic outputs that are thought to modulate neuronal activity through pre- and postsynaptic interactions. In this study, we developed an in silico multicellular model of the SCN clock to investigate the impact of astrocytes in modulating neuronal activity and affecting key clock properties such as circadian rhythmicity, period, and synchronization. The model predicted that astrocytes could alter the rhythmic activity of neurons via bidirectional interactions at tripartite synapses. Specifically, astrocyte-regulated extracellular glutamate was predicted to increase neuropeptide signaling from neurons. Consistent with experimental results, we found that astrocytes could increase the circadian period and enhance neural synchronization according to their endogenous circadian period. The impact of astrocytic modulation of circadian rhythm amplitude, period, and synchronization was predicted to be strongest when astrocytes had periods between 0 and 2 h longer than neurons. Increasing the number of neurons coupled to the astrocyte also increased its impact on period modulation and synchrony. These computational results suggest that signals that modulate astrocytic rhythms or signaling (e.g., as a function of season, age, or treatment) could cause disruptions in circadian rhythm or serve as putative therapeutic targets.

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Cholecystokinin (CCK)-expressing neurons in the suprachiasmatic nucleus: innervation, light responsiveness and entrainment in CCK-deficient mice

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2010.07385.x ◽

2010 ◽

Vol 32 (6) ◽

pp. 1006-1017 ◽

Cited By ~ 9

Author(s):

Jens Hannibal ◽

Christian Hundahl ◽

Jan Fahrenkrug ◽

Jens F. Rehfeld ◽

Lennart Friis-Hansen

Keyword(s):

Suprachiasmatic Nucleus ◽

Deficient Mice

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Radial maze performance, open-field and elevated plus-maze behaviors in Fyn-kinase deficient mice: Further evidence for increased fearfulness

Molecular Brain Research ◽

10.1016/0169-328x(95)00300-h ◽

1996 ◽

Vol 37 (1-2) ◽

pp. 145-150 ◽

Cited By ~ 51

Author(s):

Tsuyoshi Miyakawa ◽

Takeshi Yagi ◽

Akira Kagiyama ◽

Hiroaki Niki

Keyword(s):

Open Field ◽

Radial Maze ◽

Elevated Plus Maze ◽

Maze Performance ◽

Fyn Kinase ◽

Plus Maze ◽

Radial Maze Performance ◽

Deficient Mice

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Disruption of the Suprachiasmatic Nucleus in Fibroblast Growth Factor Signaling-Deficient Mice

Frontiers in Endocrinology ◽

10.3389/fendo.2016.00011 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 3

Author(s):

Ann V. Miller ◽

Scott I. Kavanaugh ◽

Pei-San Tsai

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Suprachiasmatic Nucleus ◽

Growth Factor Signaling ◽

Fibroblast Growth ◽

Fibroblast Growth Factor Signaling ◽

Deficient Mice

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Correction to Supporting Information for Smyllie et al., Temporally chimeric mice reveal flexibility of circadian period-setting in the suprachiasmatic nucleus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2113007118 ◽

2021 ◽

Vol 118 (35) ◽

pp. e2113007118

Keyword(s):

Suprachiasmatic Nucleus ◽

Circadian Period ◽

Chimeric Mice

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Abnormal Synaptic Transmission in the Olfactory Bulb of Fyn-Kinase–Deficient Mice

Journal of Neurophysiology ◽

10.1152/jn.1998.79.1.137 ◽

1998 ◽

Vol 79 (1) ◽

pp. 137-142 ◽

Cited By ~ 26

Author(s):

Hiromasa Kitazawa ◽

Takeshi Yagi ◽

Tsuyoshi Miyakawa ◽

Hiroaki Niki ◽

Nobufumi Kawai

Keyword(s):

Olfactory Bulb ◽

Synaptic Transmission ◽

Metabotropic Glutamate Receptors ◽

Granule Cells ◽

Long Term Potentiation ◽

Lateral Olfactory Tract ◽

Metabotropic Glutamate ◽

Olfactory Tract ◽

Fyn Kinase ◽

Deficient Mice

Kitazawa, Hiromasa, Takeshi Yagi, Tsuyoshi Miyakawa, Hiroaki Niki, and Nobufumi Kawai. Abnormal synaptic transmission in the olfactory bulb of Fyn-kinase–deficient mice. J. Neurophysiol. 79: 137–142, 1998. We studied synaptic transmission in the granule cells in the olfactory bulb of the homozygous Fyn (a nonreceptor type tyrosine kinase)-deficient ( fyn z/ fyn z) and heterozygous Fyn-deficient (+/ fyn z) mice by using slice preparations from the olfactory bulb. Stimulation to the lateral olfactory tract and/or centrifugal fibers to the olfactory bulb evoked field excitatory postsynaptic potentials (fEPSPs) in the granule cells. In +/ fyn z mice, fEPSPs were augmented by bicuculline, a γ-aminobutyric acid (GABAA) antagonist and picrotoxin, whereas fEPSPs in fyn z/ fyn z mice were much less sensitive to bicuculline and picrotoxin. Application of d-2-amino-5-phosphonopentanoic acid had no effect but 6-cyano-7-nitroquinoxaline-2,3-dione produced almost complete block of fEPSPs in both +/ fyn z mice and fyn z/ fyn z mice. (1S, 3R)-1-aminocyclo-pentane-1.3-dicarboxylate, an agonist of metabotropic glutamate receptors caused a similar depression of fEPSPs in both +/ fyn z and fyn z/ fyn z mice. In +/ fyn z mice tetanic stimulation to the lateral olfactory tract and/or centrifugal fibers induced N-methyl-d-aspartate (NMDA)-dependent long-term potentiation (LTP) of fEPSPs, whereas LTP was impaired in fyn z/ fyn z mice. Our results demonstrate altered functions of GABAA and NMDA receptors in the olfactory system of Fyn-deficient mice.

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