Tonically active GABAA receptors: modulating gain and maintaining the tone

Semyanov, Alexey; Walker, Matthew C.; Kullmann, Dimitri M.; Silver, R. Angus

doi:10.1016/j.tins.2004.03.005

Cited by 677 publications

(649 citation statements)

References 71 publications

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“…17,18 The phasic component results from the brief pulse of action potential-dependent or -independent GABA release and is mediated by synaptic GABA A Rs. In contrast, tonic inhibition is caused by low ambient GABA levels acting predominantly on extrasynaptic GA-BA A Rs.…”

Section: Dnactrib Mice Display a Low-anxiety Phenotype And Respond Pomentioning

confidence: 99%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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Activin, a member of the transforming growth factor-b superfamily, affords neuroprotection in acute brain injury, but its physiological functions in normal adult brain are largely unknown. Using transgenic (tg) mice expressing a dominant-negative activin receptor mutant under the control of the CaMKIIa promoter in forebrain neurons, we identified activin as a key regulator of c-aminobutyric acid (GABA)ergic synapses and anxiety-like behavior. In the open field, wildtype (wt) and tg mice did not differ in spontaneous locomotion and exploration behavior. However, tg mice visited inner fields significantly more often than wt mice. In the light-dark exploration test, tg mice made more exits, spent significantly more time on a well-lit elevated bar and went farther away from the dark box as compared to wt mice. In addition, the anxiolytic effect of diazepam was abrogated in tg mice. Thus the disruption of activin receptor signaling produced a low-anxiety phenotype that failed to respond to benzodiazepines. In whole-cell recordings from hippocampal pyramidal cells, enhanced spontaneous GABA release, increased GABA tonus, reduced benzodiazepine sensitivity and augmented GABA B receptor function emerged as likely substrates of the low-anxiety phenotype. These data provide strong evidence that activin influences pre-and postsynaptic components of GABAergic synapses in a highly synergistic fashion. Given the crucial role of GABAergic neurotransmission in emotional states, anxiety and depression, dysfunctions of activin receptor signaling could be involved in affective disorders: and drugs affecting this pathway might show promise for psychopharmacological treatment.

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Section: Dnactrib Mice Display a Low-anxiety Phenotype And Respond Pomentioning

confidence: 99%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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“…Of unexplored, but potentially high significance in understanding modulation of GABAergic tone in the hypothalamus is the impact steroid modulators may have on tonic currents mediated by low concentrations of ambient GABA through high affinity extrasynaptic receptors. Such receptors have been studied extensively in the hippocampus and cerebellum where they have been shown to play a critical role in regulating action potential firing and input-output relationships in neurons (for review, Semyanov et al, 2004). Recently, tonic currents in oxytocin and vasopressin neurons of the SON have been thoroughly characterized.…”

Section: Future Directionsmentioning

confidence: 99%

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Henderson

2007

Neuropharmacology

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The hypothalamus, the seat of neuroendocrine control, is exquisitely sensitive to gonadal steroids. For decades it has been known that androgens, estrogens and progestins, acting through nuclear hormone receptors, elicit both organizational and activational effects in the hypothalamus and basal forebrain that are essential for reproductive function. While changes in gene expression mediated by these classical hormone pathways are paramount in governing both sexual differentiation and the neural control of reproduction, it is also clear that steroids impart critical control of neuroendocrine functions through nongenomic mechanisms. Specifically, endogenous neurosteroid derivatives of deoxycorticosterone, progesterone and testosterone, as well and synthetic anabolic androgenic steroids that are self-administered as drugs of abuse, elicit acute effects via allosteric modulation of γ-aminobutyric acid type A receptors. GABAergic transmission within the hypothalamus and basal forebrain is a key regulator of pubertal onset, the expression of sexual behaviors, pregnancy and parturition. Summarized here are the known actions of steroid modulators on GABAergic transmission within the hypothalamus/basal forebrain, with a focus on the medial preoptic area and the supraoptic/paraventricular nuclei that are known to be central players in the control of reproduction.

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“…This modulation provides a powerful mechanism for maintaining the responsiveness (output) of a neuron to diverse levels of incoming synaptic input (Mitchell and Silver, 2003;Semyanov et al, 2004). Tonic inhibition, thus, provides a mechanism of 'intrinsic homeostatic plasticity' (Mody, 2005), and cells that possess tonically active GABA receptors have an additional control of intrinsic properties through ambient levels of GABA in the extrasynaptic space.…”

Section: Tonic Inhibition and Homeostasismentioning

confidence: 99%

“…Additionally, because this is a long-lasting, tonic form of inhibition, these receptors have a low rate of desensitization. Although the exact stoichiometry is unknown, tonic inhibition in some regions is mediated, in part, by δ-containing GABA A receptors (Semyanov et al, 2004). At the level of individual cells, tonic inhibition shunts a cell by increasing conductance, alters the membrane time constant, and modulates the input-output function (gain) of a cell.…”

Section: Introductionmentioning

confidence: 99%

“…Cell-type differences have been noted in the hippocampus, with inhibitory cells having relatively large amounts of tonic inhibition. Appropriately, selectively blocking tonic inhibition in these regions increases the frequency of spontaneous inhibitory post-synaptic currents onto pyramidal cells (Semyanov et al, 2004). The expression of tonic inhibition in the complex inhibitory circuits of the cortex is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Excitability of cortical neurons depends upon a powerful tonic conductance in inhibitory networks

Krook-Magnuson

Huntsman

2005

THL

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Layer 4 of the mouse somatosensory (barrel) cortex has a diversity of interneuron cell types. Tonic inhibition in other regions is cell type-specific and mediated, in part, by δ-subunit containing, extrasynaptic, GABA A receptors. We have investigated tonic inhibition in LTS cells, a major type of inhibitory neuron, and excitatory cells in layer 4 of the mouse barrel cortex using 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridine-3-ol (THIP), a superagonist of these receptors. Bath application of 20 µM THIP produced baseline shifts, which indicates activation of tonic inhibition of both excitatory and LTS cells. The baseline shift was significantly larger in LTS cells. This finding of greater induced current in LTS cells was paralleled by a significantly greater increase in conductance with THIP application in LTS cells. The increase in conductance resulted in LTS cells requiring more current to reach threshold. Because of the differential effects of tonic inhibition on LTS cells and excitatory cells, bath application of THIP increased the network excitability, measured by multi-unit recordings. Thus, the network effect of tonic inhibition in horizontal layer 4 circuits is a paradoxical increase in excitation.

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Tonically active GABAA receptors: modulating gain and maintaining the tone

Cited by 677 publications

References 71 publications

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Excitability of cortical neurons depends upon a powerful tonic conductance in inhibitory networks

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