Cell-type specific distribution of chloride transporters in the rat suprachiasmatic nucleus

Belenky, Michael; Sollars, Patricia J.; Mount, David B.; Alper, Seth L.; Yarom, Yosef; Pickard, Gary E.

doi:10.1016/j.neuroscience.2009.11.040

Cited by 49 publications

(61 citation statements)

References 77 publications

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“…The immunohistochemistry results suggest that more NKCC1 is localized in the cell perimeter presumably in the membrane. NKCC1 activity has also been found to be critical for the GABAergic excitation observed in immature cortical neurons (Ben-Ari, 2002) and gonadotropin-releasing hormone neurons (DeFazio et al, 2002) as well as in the suprachiasmatic nucleus (Belenky et al, 2008(Belenky et al, , 2010Choi et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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Chronic Hyperosmotic Stress Converts GABAergic Inhibition into Excitation in Vasopressin and Oxytocin Neurons in the Rat

Kim¹,

Kim²,

Kim³

et al. 2011

J. Neurosci.

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In mammals, the increased secretion of arginine-vasopressin (AVP) (antidiuretic hormone) and oxytocin (natriuretic hormone) is a key physiological response to hyperosmotic stress. In this study, we examined whether chronic hyperosmotic stress weakens GABA A receptor-mediated synaptic inhibition in rat hypothalamic magnocellular neurosecretory cells (MNCs) secreting these hormones. Gramicidin-perforated recordings of MNCs in acute hypothalamic slices prepared from control rats and ones subjected to the chronic hyperosmotic stress revealed that this challenge not only attenuated the GABAergic inhibition but actually converted it into excitation. The hyperosmotic stress caused a profound depolarizing shift in the reversal potential of GABAergic response (E GABA ) in MNCs. This E GABA shift was associated with increased expression of NaϪ cotransporter 1 (NKCC1) in MNCs and was blocked by the NKCC inhibitor bumetanide as well as by decreasing NKCC activity through a reduction of extracellular sodium. Blocking central oxytocin receptors during the hyperosmotic stress prevented the switch to GABAergic excitation. Finally, intravenous injection of the GABA A receptor antagonist bicuculline lowered the plasma levels of AVP and oxytocin in rats under the chronic hyperosmotic stress. We conclude that the GABAergic responses of MNCs switch between inhibition and excitation in response to physiological needs through the regulation of transmembrane Cl Ϫ gradients.

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Section: Discussionmentioning

confidence: 99%

“…Previous work suggests that the Cl Ϫ -importing transporter NKCC1 plays a critical role in GABAergic excitation in neurons (Ben-Ari, 2002;Choi et al, 2008;Irwin and Allen, 2009;Belenky et al, 2010). To examine the role of this transporter in the depolarizing shift of E GABA in MNCs (Fig.…”

Section: Nkcc1 Contributes To the Depolarizing Shift Of E Gaba And Thmentioning

confidence: 99%

Chronic Hyperosmotic Stress Converts GABAergic Inhibition into Excitation in Vasopressin and Oxytocin Neurons in the Rat

Kim¹,

Kim²,

Kim³

et al. 2011

J. Neurosci.

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“…Chloride gradients in neurons are determined in large part by the actions of two types of chloride transporters, KCC2, which extrudes chloride, and NKCC1, which accumulates chloride into neurons (Blaesse et al 2009). In some brain regions, such as the olfactory neuroepithelium, retina, and suprachiasmatic nucleus, where GABA has been shown to be excitatory, NKCC1 protein has been detected in adult tissue (Belenky et al 2009;Kaneko et al 2004;Li et al 2008). In other neurons, such as neocortical pyramidal cells, where GABA has been shown to depolarize axons, it is unclear whether NKCC1 is expressed in adults; however, KCC2 protein is excluded from the axonal compartments (Szabadics et al 2006).…”

Section: Discussionmentioning

confidence: 99%

GABA_A receptors increase excitability and conduction velocity of cerebellar parallel fiber axons

Dellal

Luo

Otis

2012

Journal of Neurophysiology

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Dellal SS, Luo R, Otis TS. GABA A receptors increase excitability and conduction velocity of cerebellar parallel fiber axons. J Neurophysiol 107: 2958 -2970. First published February 29, 2012 doi:10.1152/jn.01028.2011In the adult mammalian brain, GABA A receptors (GABA A Rs) are responsible for the predominant forms of synaptic inhibition, but these receptors can excite neurons when the chloride equilibrium potential (E Cl ) is depolarized. In many mature neurons, GABA A Rs are found on presynaptic terminals where they exert depolarizing effects. To understand whether excitatory GABA action affects axonal function, we used transverse cerebellar slices to measure the effects of photolysis of caged GABA on the initiation and propagation of compound parallel fiber (PF) action potentials (APs). Photolysis of caged GABA increased the amplitude and conduction velocity of PF APs; GABA reuptake blockers and a positive modulator of GABA A Rs enhanced these effects. In contrast, a modulator selective for ␦-subunit-containing GABA A Rs did not enhance these effects and responsiveness remained in ␦ Ϫ/Ϫ mice, arguing that ␦-subunit-containing GABA A Rs are not required. Synaptically released GABA also increased PF excitability, indicating that the mechanism is engaged by physiological signals. A Hodgkin-Huxleystyle compartmental model of the PF axon and granule cell body was constructed, and this model recapitulated the GABA-dependent decrease in AP threshold and the increase in conduction velocity, features that were sensitive to E Cl and to the voltage dependence of sodium channel inactivation. The model also predicts that axonal GABA A Rs could affect orthodromic spike initiation. We conclude that GABA acting on cerebellar PFs facilitates both spike generation and propagation, allowing axons of granule cells to passively integrate signals from inhibitory interneurons and influence information flow in the input layer to the cerebellar cortex.␥-aminobutyric acid; presynaptic modulation; axonal excitability; ␦-subunit; fiber volley; caged ␥-aminobutyric acid THE CLASSICAL STUDIES OF MUSCLE afferent inputs to spinal motor neurons that gave rise to the concept of presynaptic inhibition also eventually led to the first identification of presynaptic GABA A receptors (GABA A Rs) (Eccles et al. 1963). Subsequent work by many laboratories demonstrated that this GABA A R-mediated presynaptic inhibition results from a depolarizing action of GABA on presynaptic afferent terminals (Rudomin and Schmidt 1999). Since those initial findings, GABA A Rs have been observed on presynaptic terminals in a variety of brain regions, including auditory brain stem, ventral tegmental area, hypothalamus, amygdala, hippocampus, cerebellum, and cortex, and in most of these locations GABA has been found to be depolarizing ( Although there have been many studies on the consequences of presynaptic GABA A Rs on synaptic transmission, relatively little is known about whether these receptors affect axonal excitability. To directly test whether transient acti...

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“…We reasoned that preferential GABA excitation in the D-SCN (19) could contribute to the speed of the Bmal1 oscillation frequency. The GABA excitation is caused by enhanced expression of the neuronal chloride importer Nkcc1 compared with chloride exporters, especially Kcc2 (29), leading to increased intracellular chloride and reversing the polarity of a cell's response to GABA from inhibition to excitation in the SCN (20,30). In isolated SCN subregion cultures, chronic application of the chloride importer inhibitor furosemide (Furo, 30 μM) increased the period of Bmal1-ELuc oscillations in the D-SCN, but not in the V-SCN, compared with the control condition before drug application (P < 0.01, paired t test; Fig.…”

Section: Day-length Modulation Of Gaba a Connection By Adjustment Ofmentioning

confidence: 99%

GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time

Myung

Hong

DeWoskin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

142

229

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The mammalian suprachiasmatic nucleus (SCN) forms not only the master circadian clock but also a seasonal clock. This neural network of ∼10,000 circadian oscillators encodes season-dependent day-length changes through a largely unknown mechanism. We show that region-intrinsic changes in the SCN fine-tune the degree of network synchrony and reorganize the phase relationship among circadian oscillators to represent day length. We measure oscillations of the clock gene Bmal1, at single-cell and regional levels in cultured SCN explanted from animals raised under short or long days. Coupling estimation using the Kuramoto framework reveals that the network has couplings that can be both phase-attractive (synchronizing) and -repulsive (desynchronizing). The phase gap between the dorsal and ventral regions increases and the overall period of the SCN shortens with longer day length. We find that one of the underlying physiological mechanisms is the modulation of the intracellular chloride concentration, which can adjust the strength and polarity of the ionotropic GABA A -mediated synaptic input. We show that increasing daylength changes the pattern of chloride transporter expression, yielding more excitatory GABA synaptic input, and that blocking GABA A signaling or the chloride transporter disrupts the unique phase and period organization induced by the day length. We test the consequences of this tunable GABA coupling in the context of excitation-inhibition balance through detailed realistic modeling. These results indicate that the network encoding of seasonal time is controlled by modulation of intracellular chloride, which determines the phase relationship among and period difference between the dorsal and ventral SCN.day-length encoding | repulsive coupling | SCN | GABA | chloride T he physiological and behavioral rhythms of all life on earth are bound to the Earth's rotational cycle of ∼24 h. This fundamental rhythm is also affected by the planet's slanted rotational axis, which causes seasonal variations in the length of the day. How life has adapted to anticipate this yearly rhythm is still debated.The suprachiasmatic nucleus (SCN), the central circadian (∼24 h) pacemaker in mammals, consists of ∼10,000 "clock" neurons. These single-cell clocks maintain endogenous rhythms by autoregulatory feedback loops of genes including period (Per) and brain and muscle Arnt-like 1 (Bmal1) (1). Although it was speculated that seasonal rhythms might be encoded in a single cell (2), single-cell oscillations remain similar regardless of the seasonal time that the SCN tissue encodes (3). Seasonal timing is thus proposed to be encoded in the network of the SCN (4-7) through spatial reorganization of the relative phases of clocks within individual cells (8-10). Subsets of SCN clocks form phase clusters (11) that map approximately to dorsal (shell, D-SCN) and ventral (core, V-SCN) regions of the SCN. When measured through a luciferase reporter monitoring oscillations in the Bmal1 gene, the D-SCN and V-SCN clusters show a phase gap, ...

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Cell-type specific distribution of chloride transporters in the rat suprachiasmatic nucleus

Cited by 49 publications

References 77 publications

Chronic Hyperosmotic Stress Converts GABAergic Inhibition into Excitation in Vasopressin and Oxytocin Neurons in the Rat

Chronic Hyperosmotic Stress Converts GABAergic Inhibition into Excitation in Vasopressin and Oxytocin Neurons in the Rat

GABA_A receptors increase excitability and conduction velocity of cerebellar parallel fiber axons

GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time

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Cell-type specific distribution of chloride transporters in the rat suprachiasmatic nucleus

Cited by 49 publications

References 77 publications

Chronic Hyperosmotic Stress Converts GABAergic Inhibition into Excitation in Vasopressin and Oxytocin Neurons in the Rat

Chronic Hyperosmotic Stress Converts GABAergic Inhibition into Excitation in Vasopressin and Oxytocin Neurons in the Rat

GABAA receptors increase excitability and conduction velocity of cerebellar parallel fiber axons

GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time

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Product

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GABA_A receptors increase excitability and conduction velocity of cerebellar parallel fiber axons