Regulation of intracellular Cl- levels by Na(+)-dependent Cl- cotransport distinguishes depolarizing from hyperpolarizing GABAA receptor-mediated responses in spinal neurons

Rohrbough, Jeffrey; Spitzer, Nicholas C.

doi:10.1523/jneurosci.16-01-00082.1996

Cited by 215 publications

(168 citation statements)

References 53 publications

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“…Consistent with previous studies, bumetanide reduced the GABA-induced membrane depolarization in VS-3 neurons by 6.7 mV. For example, tadpole Rohon-Beard neuron reversal potential for GABA was about 10 mV (Rohrbough and Spitzer 1996) and rat hippocampal neurons about 18 mV more negative after bumetanide treatment (Sipilä et al 2006). In previous studies Values in each cell are means Ϯ SD.…”

Section: Chloride Transporters Do Not Reduce the Excitatory Effect Ofsupporting

confidence: 89%

“…This secondary active transporter is also responsible for the high intracellular Cl Ϫ gradient in amphibian dorsal root ganglion neurons and Rohon-Beard neurons, which respond to GABA A receptor activation with depolarization (Alvarez-Leefmans et al 1988, 2001Rohrbough and Spitzer 1996). Consistent with previous studies, bumetanide reduced the GABA-induced membrane depolarization in VS-3 neurons by 6.7 mV.…”

Section: Chloride Transporters Do Not Reduce the Excitatory Effect Ofsupporting

confidence: 81%

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Random Stimulation of Spider Mechanosensory Neurons Reveals Long-Lasting Excitation by GABA and Muscimol

Pfeiffer

Panek²,

Höger³

et al. 2009

Journal of Neurophysiology

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Pfeiffer K, Panek I, Hö ger U, French AS, Torkkeli PH. Random stimulation of spider mechanosensory neurons reveals long-lasting excitation by GABA and muscimol. J Neurophysiol 101: 54 -66, 2009. First published November 12, 2008; doi:10.1152/jn.91020.2008. ␥-Aminobutyric acid type A (GABA A ) receptor activation inhibits many primary afferent neurons by depolarization and increased membrane conductance. Deterministic (step and sinusoidal) functions are commonly used as stimuli to test such inhibition. We found that when the VS-3 mechanosensory neurons innervating the spider lyriform slitsense organ were stimulated by randomly varying white-noise mechanical or electrical signals, their responses to GABA A receptor agonists were more complex than the inhibition observed during deterministic stimulation. Instead, there was rapid excitation, then brief inhibition, followed by long-lasting excitation. During the final excitatory phase, VS-3 neuron sensitivity to high-frequency signals increased selectively and their linear information capacity also increased. Using experimental and simulation approaches we found that the excitatory effect could also be achieved by depolarizing the neurons without GABA application and that excitation could override the inhibitory effect produced by increased membrane conductance (shunting). When the VS-3 neurons were exposed to bumetanide, an antagonist of the Cl Ϫ transporter NKCC1, the GABA-induced depolarization decreased without any change in firing rate, suggesting that the effects of GABA can be maintained for a long time without additional Cl Ϫ influx. Our results show that the VS-3 neuron's response to GABA depends profoundly on the type of signals the neuron is conveying while the transmitter binds to its receptors.

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Section: Chloride Transporters Do Not Reduce the Excitatory Effect Ofsupporting

confidence: 89%

Section: Chloride Transporters Do Not Reduce the Excitatory Effect Ofsupporting

confidence: 81%

Random Stimulation of Spider Mechanosensory Neurons Reveals Long-Lasting Excitation by GABA and Muscimol

Pfeiffer

Panek²,

Höger³

et al. 2009

Journal of Neurophysiology

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“…However, this study does not address the mechanism by which this factor regulates intracellular chloride concentration. Possible mechanisms include regulation of a large number of proteins, including cation-chloride cotransporters (12), namely the Na + -K + -2Cl − cotransporters that increase [Cl − ] i (10,(31)(32)(33)(34)(35) (42), and a variety of chloride channels (13). In contrast to the hippocampus, RGCs do not express Na + -K + -2Cl − cotransporter 1 (23) and they do not express Cl − /HCO 3 + exchangers until later in development (43).…”

Section: Discussionmentioning

confidence: 99%

Non–cell-autonomous factor induces the transition from excitatory to inhibitory GABA signaling in retina independent of activity

Barkis

Ford²,

Feller³

2010

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

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During development, the effect of activating GABA A receptors switches from depolarizing to hyperpolarizing. Several environmental factors have been implicated in the timing of this GABA switch, including neural activity, although these observations remain controversial. By using acutely isolated retinas from KO mice and pharmacological manipulations in retinal explants, we demonstrate that the timing of the GABA switch in retinal ganglion cells (RGCs) is unaffected by blockade of specific neurotransmitter receptors or global activity. In contrast to RGCs in the intact retina, purified RGCs remain depolarized by GABA, indicating that the GABA switch is not cell-autonomous. Indeed, purified RGCs cocultured with dissociated cells from the superior colliculus or cultured in media conditioned by superior collicular cells undergo a normal switch. Thus, a diffusible signal that acts independent of local circuit activity regulates the maturation of GABAergic inhibition in mouse RGCs.A lthough GABA is the principal inhibitory neurotransmitter in the mature CNS, it is a robust source of excitation during development that is important for many developmental processes (1-4). The transition from excitatory to inhibitory action of GABA has been observed in a number of neural circuits and in many vertebrate species (5, 6) and the primary mechanisms underlying the switch are fairly well understood (7-11; reviewed in refs. 12-14). However, whether the timing of the GABA switch is modulated by local circuit activity (8,(15)(16)(17)(18) or occurs independent of activity (19,20) and is therefore intrinsic to developmental program of the cell remains controversial.Retinal ganglion cells (RGCs) undergo a switch in their response to GABA during the first two postnatal weeks of development (21-23). In vivo recordings in zebrafish demonstrate that the timing of the GABA switch is critical for the timing of the development of light responses (24) and therefore might be linked to the onset of visual experience. Chronic blockade of GABA A receptors (GABA A Rs) in turtle retina prevents the normal maturation of spontaneous firing patterns termed retinal waves and the maturation of adult-like chloride gradients, implicating early GABA signaling in the normal maturation of inhibitory circuits in retina (15). Based on these results, it has been proposed that the maturation of GABAergic inhibition is influenced by local network activity and is critical for the cessation of retinal waves (25).Here we explore factors that influence the timing of the GABA switch in mouse RGCs. By using three different preparations, we test whether the timing of the GABA switch is regulated by (i) local circuit activity in the retina, (ii) an intrinsic developmental program, or (iii) a diffusible, non-cell autonomous factor that operates independent of retinal activity. Results GABA Switch Occurs Normally in Nicotinic Acetylcholine Receptor-KORetinas. The timing of the GABA switch in retinal neurons in the ganglion cell layer (GCL) was determined by calcium imagi...

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“…These results suggested that neuronal development might be mediated by the GABA A receptors containing the α2 and α3 subunits, and the GABAergic inhibitory transmission is mediated by the receptors including the α1 and α6 subunits. Although it is generally considered that the changes in GABAergic roles may be reflected by the Cl -reversal potential [10,45,47,52,53], the above suggested that the subunit-composition might partially related to the expression of roles.…”

Section: Relationship Between Gabaergic Roles In the Developing Cerebmentioning

confidence: 99%

Transient expression of GABAA receptor α2 and α3 subunits in differentiating cerebellar neurons

Takayama

Inoue

2004

Developmental Brain Research

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In the adult mammalian brain, synaptic transmission mediated by γ-amino butyric acid (GABA) plays a role in inhibition of excitatory synaptic transmission. During brain development, GABA is involved in brain morphogenesis. To clarify how GABA exerts its effect on immature neurons, we examined the expression of the GABA A receptor α2 and α3 subunits, which are abundantly expressed before α1 and α6 subunits appear, in the developing mouse cerebellum using in situ hybridization. Proliferating neuronal precursors in the ventricular zone and external granular layer expressed neither α2 nor α3 subunits.Hybridization signals for the α2 and α3 subunit mRNAs first appeared in the differentiating zone at embryonic day 13 (E13). The α2 subunit was detected in the migrating and differentiating granule cells and cerebellar nucleus neurons until postnatal day 14 (P14).Hybridization signals for the α3 subunit mRNA, on the other hand, were localized in the developing Purkinje cells and cerebellar nucleus neurons, and disappeared from Purkinje cells by the end of first postnatal week. Taken together, this indicated that the α2 and α3 subunits were abundantly expressed in distinct types of cerebellar neurons after completing cell proliferation while forming the neural network. These results suggest that GABA might extrasynaptically activate the GABA A receptors containing α2 and/or α3 subunits on the differentiating neurons before finishing the formation of synapses and networks, and could be involved in neuronal differentiation and maturation in the cerebellum. Classification TermsTheme A: Development and Regeneration Topic: Neurotransmitter systems and channels

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Regulation of intracellular Cl- levels by Na(+)-dependent Cl- cotransport distinguishes depolarizing from hyperpolarizing GABAA receptor-mediated responses in spinal neurons

Cited by 215 publications

References 53 publications

Random Stimulation of Spider Mechanosensory Neurons Reveals Long-Lasting Excitation by GABA and Muscimol

Random Stimulation of Spider Mechanosensory Neurons Reveals Long-Lasting Excitation by GABA and Muscimol

Non–cell-autonomous factor induces the transition from excitatory to inhibitory GABA signaling in retina independent of activity

Transient expression of GABAA receptor α2 and α3 subunits in differentiating cerebellar neurons

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