Tonic GABAergic Inhibition Research Articles

A Reinforcing Circuit Action of Extrasynaptic GABAA Receptor Modulators on Cerebellar Granule Cell Inhibition

GABAA receptors (GABARs) are the targets of a wide variety of modulatory drugs which enhance chloride flux through GABAR ion channels. Certain GABAR modulators appear to acutely enhance the function of δ subunit-containing GABAR subtypes responsible for tonic forms of inhibition. Here we identify a reinforcing circuit mechanism by which these drugs, in addition to directly enhancing GABAR function, also increase GABA release. Electrophysiological recordings in cerebellar slices from rats homozygous for the ethanol-hypersensitive (α6100Q) allele show that modulators and agonists selective for δ-containing GABARs such as THDOC, ethanol and THIP (gaboxadol) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in granule cells. Ethanol fails to augment granule cell sIPSC frequency in the presence of glutamate receptor antagonists, indicating that circuit mechanisms involving granule cell output contribute to ethanol-enhancement of synaptic inhibition. Additionally, GABAR antagonists decrease ethanol-induced enhancement of Golgi cell firing. Consistent with a role for glutamatergic inputs, THIP-induced increases in Golgi cell firing are abolished by glutamate receptor antagonists. Moreover, THIP enhances the frequency of spontaneous excitatory postsynaptic currents in Golgi cells. Analyses of knockout mice indicate that δ subunit-containing GABARs are required for enhancing GABA release in the presence of ethanol and THIP. The limited expression of the GABAR δ subunit protein within the cerebellar cortex suggests that an indirect, circuit mechanism is responsible for stimulating Golgi cell GABA release by drugs selective for extrasynaptic isoforms of GABARs. Such circuit effects reinforce direct actions of these positive modulators on tonic GABAergic inhibition and are likely to contribute to the potent effect of these compounds as nervous system depressants.

GABAergic tonic inhibition is regulated by developmental age and epilepsy in the dentate gyrus

γ-Aminobutyric acid (GABA) spillover from synaptic cleft activates extrasynaptic GABAA receptor and results in a tonic inhibition, which induces a background inhibitory effect to stabilize the membrane potential of the neuronal cells. However, the role of tonic inhibition and how it can be regulated during brain development and epileptic state remain elusive. By whole-cell patch-clamp recording on the granule cell in the dentate gyrus, we recorded tonic conductance to investigate the level of tonic inhibition in these two critical periods. According to our observation, an age-dependent increase in tonic conductance was observed. Furthermore, a change in tonic inhibition was also found in a chronic epileptic animal model, indicating that the alteration in tonic inhibition after epilepsy induction persists for a long duration to modulate neuronal activities. The present results show that tonic inhibition is altered during brain development and a chronic epileptic condition, indicating a role of the tonic inhibitory effect in both the critical periods.

Layer- and cell-type-specific tonic GABAergic inhibition of pyramidal neurons in the rat visual cortex

Tonic inhibition mediated by persistent activation of γ-aminobutyric acidA (GABAA) receptors by ambient GABA plays a crucial role in the regulation of network excitability and neuronal signal processing. Varying degrees in the strength of tonic inhibition were detected across different cell types throughout the brain. Since sensory information flows through cortical layers in a specific order, the characteristics of tonic inhibition in different cortical layers are of interest. Therefore, we examined the properties of tonic inhibition in pyramidal neurons (PyNs) throughout the rat visual cortex. Layer 2/3 PyNs and burst-spiking PyNs in layers 5 and 6 showed prominent tonic GABAA currents. Tonic GABAA currents in layer 4 star PyNs and regular-spiking PyNs in layers 5 and 6 were much weaker. The magnitude of tonic currents correlated well with the inhibition of spike generation. The amplitude of tonic GABAA currents measured with bicuculline and gabazine, the two different GABAA receptor blockers, did not differ. The differences in the expression levels of extrasynaptic GABAA receptors might be the major contributor to the differences in tonic GABAA currents among cell types. Furthermore, α5 subunits might contribute significantly to tonic currents in infragranular burst-spiking PyNs, especially in layer 5. These results suggest that ambient GABA might exert differential effects on the neuronal integration in a layer- and cell-type-specific manner and thus contribute to the processing of sensory properties by selectively tuning the signals flowing through the visual cortex.

Overnight Fasting Regulates Inhibitory Tone to Cholinergic Neurons of the Dorsomedial Nucleus of the Hypothalamus

The dorsomedial nucleus of the hypothalamus (DMH) contributes to the regulation of overall energy homeostasis by modulating energy intake as well as energy expenditure. Despite the importance of the DMH in the control of energy balance, DMH-specific genetic markers or neuronal subtypes are poorly defined. Here we demonstrate the presence of cholinergic neurons in the DMH using genetically modified mice that express enhanced green florescent protein (eGFP) selectively in choline acetyltransferase (Chat)-neurons. Overnight food deprivation increases the activity of DMH cholinergic neurons, as shown by induction of fos protein and a significant shift in the baseline resting membrane potential. DMH cholinergic neurons receive both glutamatergic and GABAergic synaptic input, but the activation of these neurons by an overnight fast is due entirely to decreased inhibitory tone. The decreased inhibition is associated with decreased frequency and amplitude of GABAergic synaptic currents in the cholinergic DMH neurons, while glutamatergic synaptic transmission is not altered. As neither the frequency nor amplitude of miniature GABAergic or glutamatergic postsynaptic currents is affected by overnight food deprivation, the fasting-induced decrease in inhibitory tone to cholinergic neurons is dependent on superthreshold activity of GABAergic inputs. This study reveals that cholinergic neurons in the DMH readily sense the availability of nutrients and respond to overnight fasting via decreased GABAergic inhibitory tone. As such, altered synaptic as well as neuronal activity of DMH cholinergic neurons may play a critical role in the regulation of overall energy homeostasis.

Monoterpene α-thujone exerts a differential inhibitory action on GABAA receptors implicated in phasic and tonic GABAergic inhibition

A monoterpene ketone, α-thujone originally attracted attention as a major natural ingredient of absinthe and was suspected to cause adverse effects such as hallucinations and seizures in persons excessively consuming this beverage. Although subsequent studies ruled out any major role of α-thujone in the “absynthism”, it was found that at high doses it may induce epileptic activity pointing to an interaction with GABAergic inhibition. Indeed, subsequent studies, including those from this laboratory, showed that α-thujone inhibits GABAergic currents. However, GABAA receptors are extremely heterogeneous and in the present study we have investigated the effect of α-thujone on different recombinant GABAA receptors (α1β2γ2L, α1β2, α1β2δ and α4β2δ) relevant to phasic or tonic forms of inhibition. We report that α-thujone inhibits all considered receptor types by a qualitatively similar mechanism but the strongest effect is observed for α1β2δ receptors, suggesting that tonic currents might be more sensitive to α-thujone than the phasic ones. Moreover, we demonstrate that tonic currents, mimicked by response to a submicromollar GABA concentration (0.3μM) in cultured neurons, showed a substantially larger sensitivity to α-thujone than responses elicited by higher [GABA] (more similar to phasic currents) or Inhibitory Postsynaptic Currents in the same preparation. Importantly, the extent of tonic current inhibition by α-thujone was as strong as in the case of currents mediated by α1β2δ receptors. Altogether, these data provide evidence that different GABAA receptor subtypes show distinct sensitivities to α-thujone and suggest that this compound may differentially affect tonic and phasic components of GABAergic inhibition.

Altered GABA and somatostatin modulation of proprioceptive feedback after spinal cord injury in lamprey

While various changes occur after spinal cord lesions, their influence on functional recovery is generally unclear. We have shown changes in proprioceptor and locomotor network properties below lesion sites in the lamprey spinal cord. The proprioceptive system offers a particularly tractable model for analyzing these changes. Here, we have sought evidence for changes in neuromodulatory effects below lesion sites by comparing the effects of gamma-aminobutyric acid (GABA) and somatostatin, both of which are located around the edge cells, on proprioceptive responses in lesioned and unlesioned spinal cords.Exogenously applied GABA significantly reduced or abolished bending-evoked responses in unlesioned animals. In lesioned animals bending-evoked responses were stronger and certain of the effects of exogenously applied GABA were reduced. However, blocking endogenous GABA with bicuculline significantly potentiated responses in lesioned but not unlesioned animals. This suggested that the potentiated responses in lesioned animals were nevertheless associated with stronger tonic GABAergic inhibition. There were significant differences in these effects when lesioned animals were separated on the basis of their degree of recovery: notably, bicuculline only potentiated responses in animals that recovered good locomotor function, suggesting a need for raised endogenous GABA levels. Somatostatin alone did not affect edge cell responses in lesioned or unlesioned animals, but in lesioned animals it reduced and thus further weakened the inhibitory effects of GABA.There are thus multiple changes in sensory modulation in the lesioned spinal cord, and differences in these effects may influence the degree of recovery.

Methods for recording and measuring tonic GABAA receptor-mediated inhibition

Tonic inhibitory conductances mediated by GABAA receptors have now been identified and characterized in many different brain regions. Most experimental studies of tonic GABAergic inhibition have been carried out using acute brain slice preparations but tonic currents have been recorded under a variety of different conditions. This diversity of recording conditions is likely to impact upon many of the factors responsible for controlling tonic inhibition and can make comparison between different studies difficult. In this review, we will firstly consider how various experimental conditions, including age of animal, recording temperature and solution composition, are likely to influence tonic GABAA conductances. We will then consider some technical considerations related to how the tonic conductance is measured and subsequently analyzed, including how the use of current noise may provide a complementary and reliable method for quantifying changes in tonic current.

Rapid regulation of tonic GABA currents in cultured rat hippocampal neurons

Subacute and chronic changes in tonic GABAergic inhibition occur in human and experimental epilepsy. Less is known about how tonic inhibition is modulated over shorter time frames (seconds). We measured endogenous tonic GABA currents from cultured rat hippocampal neurons to evaluate how they are affected by 1) transient increases in extracellular GABA concentration ([GABA]), 2) transient postsynaptic depolarization, and 3) depolarization of presynaptic cells. Transient increases in [GABA] (1 μM) reduced tonic currents; this reduction resulted from GABA-induced shifts in the reversal potential for GABA currents (E(GABA)). Transient depolarization of postsynaptic neurons reversed the effects of exogenous GABA and potentiated tonic currents. The voltage-dependent potentiation of tonic GABA currents was independent of E(GABA) shifts and represented postdepolarization potentiation (PDP), an intrinsic GABA(A) receptor property (Ransom CB, Wu Y, Richerson GB. J Neurosci 30: 7672-7684, 2010). Inhibition of vesicular GABA release with concanamycin A (ConA) did not affect tonic currents. In ConA-treated cells, transient application of 12 mM K(+) to depolarize presynaptic neurons and glia produced a persistent increase in tonic current amplitude. The K(+)-induced increase in tonic current was reversibly inhibited by SKF89976a (40 μM), indicating that this was caused by nonvesicular GABA release from GABA transporter type 1 (GAT1). Nonvesicular GABA release due to GAT1 reversal also occurred in acute hippocampal brain slices. Our results indicate that tonic GABA currents are rapidly regulated by GABA-induced changes in intracellular Cl(-) concentration, PDP of extrasynaptic GABA(A) receptors, and nonvesicular GABA release. These mechanisms may influence tonic inhibition during seizures when neurons are robustly depolarized and extracellular GABA and K(+) concentrations are elevated.

Alpha-asarone from Acorus gramineus alleviates epilepsy by modulating A-Type GABA receptors

Alpha (α)-asarone is a major effective compound isolated from the Chinese medicinal herb Acorus gramineus, which is widely used in clinical practice as an antiepileptic drug; however, its mechanism of action remains unclear. In this study, we have characterized the action of α-asarone on the excitability of rat hippocampal neurons in culture and on the epileptic activity induced by pentylenetetrazole or kainate injection in vivo. Under cell-attached configuration, the firing rate of spontaneous spiking was inhibited by application of α-asarone, which was maintained in the Mg2+-free solution. Under whole-cell configuration, α-asarone induced inward currents in a concentration-dependent manner with an EC50 of 248 ± 33 μM, which was inhibited by a GABAA receptor blocker picotoxin and a competitive GABAA receptor antagonist bicuculline but not a specific glycine receptor inhibitor strychnine. Measurement of tonic GABA currents and miniature spontaneous inhibitory postsynaptic currents indicated that α-asarone enhanced tonic GABAergic inhibition while left phasic GABAergic inhibition unaffected. In both pentylenetetrazole and kainate seizure models, α-asarone suppressed epileptic activity of mice by prolonging the latency to clonic and tonic seizures and reducing the mortality as well as the susceptibility to seizure in vivo presumably dependent on the activation of GABAA receptors. In summary, our results suggest that α-asarone inhibits the activity of hippocampal neurons and produces antiepileptic effect in central nervous system through enhancing tonic GABAergic inhibition.

Brainstem injection of lidocaine releases the descending pain-inhibitory mechanisms in a rat model of mononeuropathy

Lidocaine injections in the rostral ventromedial medulla (RVM) have been shown to produce significant reduction of neuropathic manifestations in rats. This effect has been attributed to selective block of a pain descending facilitatory system, responsible for chronic pain. However, recent observations from our laboratory did not provide confirmation to this hypothesis. We aimed, therefore, to investigate the spinal synaptic mechanisms activated by lidocaine injections in the RVM.Rats were subjected, under deep anesthesia, to the induction of mononeuropathy on one hindpaw, and to the stereotaxic implantation of chronic cannulae in the RVM for the injection of lidocaine or GABA antagonists. Implanted intrathecal catheter in the lumbosacral space was used for the injection of specific antagonists to GABA, 5HT, glycine, noreadrenaline and dopamine, prior to lidocaine. Tactile and cold hyperreactivity and heat hyperalgesia were assessed using von Frey hair filaments, acetone drop test and heat-induced paw withdrawal, respectively.Lidocaine injections produced significant inhibition of all neuropathic manifestations. Intrathecal injection of antagonists to GABA (bicucullin, picrotoxin and saclofen), serotonin 5HT1–2 (ketanserin and methysergide) and α- (phentoalmine, yohimbine) and β- (propranolol) adrenergic receptors, suppressed the lidocaine inhibitory effects; while partial or no attenuation were observed following pretreatment with glycine and dopamine D2/3 antagonists. Comparable effects were observed with RVM injection of GABA antagonists.Lidocaine injection in the RVM results in a release of the descending pain-inhibitory systems from a tonic gabaergic inhibition. This descending system involves the activation of gabaergic, serotonergic and adrenergic mechanisms at the level of the spinal dorsal horn.

Enhanced activation of sympathetic nerve activity and arterial pressure by the hypothalamic paraventricular nucleus in obese Zucker rats

Adult obese Zucker rats (OZR) have elevated sympathetic nerve activity (SNA) and mean arterial pressure (MAP) that is driven by the rostral ventrolateral medulla (RVLM), and exaggerated sympatho‐excitatory reflexes associated with an enhanced ability of glutamate to activate the RVLM. Because the PVN contributes to basal SNA and MAP via an excitatory projection to RVLM, we sought to determine whether the PVN may contribute to the elevated SNA and MAP observed in OZR vs. lean Zucker rats (LZR). We also sought to determine whether the ability of the PVN to increase SNA and MAP was exaggerated in OZR vs. LZR. Adult male rats were anesthetized with urethane (1.5 g/kg, iv), ventilated, and paralyzed to record splanchnic SNA and MAP. Compared to LZR, OZR had higher SNA (1.7±0.3 vs. 0.6±0.2 μV, P<0.05) and MAP (128±5 vs. 101±8 mmHg, P<0.05). Inhibition of PVN (muscimol; 100 pmol) evoked larger decreases in AP in OZR (6) vs. LZR (7; −17±3 vs. −8±2 mmHg, P<0.05). This was not due to reduced tonic GABAergic inhibition of PVN because gabazine into PVN (100 pmol) evoked comparable rises in SNA and AP in OZR (5) and LZR (7). Activation of PVN (NMDA, 50 pmol) produced greater increases in SNA (57±3 vs. 42±6 %, P<0.05) and MAP (18±4 vs. 7±2 mmHg, P<0.05) in OZR (6) vs. LZR (7). These data suggest that the PVN contributes to the elevated AP in OZR. Exaggerated responses to activation of the PVN may be due to changes at the PVN or RVLM. Supported by NIH HL086759.

P.1.026 Sub-chronic phencyclidine alters GABAergic gene expression in rat frontal cortex: focus on tonic inhibition and its relevance to cognition

Introduction: Schizophrenia is a serious psychiatric disorder, characterised by 3 symptom domains: positive, negative and cognitive deficits. Sub-chronic administration of the psychotomimetic agent phencyclidine (PCP) has been shown to cause enduring deficits in a range of cognitive tests of relevance to schizophrenia symptomatology in the rat [1]. GABAergic dysfunction has been implicated in schizophrenia. In particular cognitive dysfunction may be linked to disturbances in GABAergic signalling which may be mimicked by the PCP model in animal studies [1]. Tonic GABAergic inhibition is mediated by extra/perisynaptically located GABAA receptors containing mainly a4, a5 and d subunits [2], as well as the GABA transporter GAT-1 and the GAD67 isoform of glutamate decarboxylase. The aim of this study was to investigate the effect of sub-chronic PCP administration on gene expression, with a particular focus on genes that regulate GABAergic tonic inhibition. Methods: Adult female Hooded-Lister rats received PCP (2mg/kg b.i.d i.p) or vehicle for 7 days, followed by a 7 day washout period before sacrifice. Brains were removed, dissected into regions according to Bregma coordinates (frontal cortex = +4.7mm to +3.2mm, striatum = +1.6mm to −0.3mm, hippocampus = −2.5mm to −3.8mm and cerebellum = −10.3mm to −12.7mm) and placed into Sigma-Aldrich RNAlaterTM solution on ice, in preparation for RNA extraction and analysis. Brain regions were homogenised in 1ml Trizol® reagent and RNA extracted using Invitrogen mini columns. After conversion to cDNA using a Qiagen reverse transcription kit, gene expression was quantified using SYBr Green qRT-PCR using a GAPDH normalising gene. The REST programme was used to analyse the data. Results: Sub-chronic PCP treatment resulted in significant (P< 0.001) reductions in the extrasynaptically located GABAA receptor subunits a4 and a5 in the frontal cortex and a significant (P< 0.01) up-regulation of d subunit in the cerebellum. Sub-chronic PCP induced a large and significant transcriptional downregulation (P< 0.001) of GAD1 and calretinin in frontal cortex. Significant reductions in GAT-1 (P< 0.05) and parvalbumin (P< 0.01) were also observed. A significant (P< 0.05) reduction in GFAP transcription was also observed in the frontal cortex. Conclusions: Sub-chronic PCP markedly reduced the transcription of GABAergic tonic inhibition genes in the frontal cortex. Large losses of parvalbumin/calretinin combined with a4 and a5 receptor subunits suggest a widespread loss of GABAergic tonic inhibition in the cortex. Lack of d subunit loss in the cortex suggests a specific population of GABAA receptors are being affected by sub-chronic PCP, most likely the a4/5+g2 group. The increase in d subunit mRNA expression in the cerebellum supports the suggestion of a brain region-specific effect of sub-chronic PCP, possibly through differential regulation of BDNF, which has been shown to be differentially regulated in different brain regions [3]. Reduction of GAT-1 and GFAP expression suggests a concurrent loss of astrocytic processes. The molecular mechanism by which PCP produces these expressional changes has yet to be elucidated. These preliminary findings suggest that a reduction in GABAergic tonic inhibition in the frontal cortex could play a role in the cognitive deficits produced in the sub-chronic PCP model.

The population firing rate in the presence of GABAergic tonic inhibition in single neurons and application to general anaesthesia

Tonic inhibition has been found experimentally in single neurons and affects the activity of neural populations. This kind of inhibition is supposed to set the background or resting level of neural activity and plays a role in the brains arousal system, e.g. during general anaesthesia. The work shows how to involve tonic inhibition in population rate-coding models by deriving a novel transfer function. The analytical and numerical study of the novel transfer function reveals the impact of tonic inhibition on the population firing rate. Finally, a first application to a recent neural field model for general anaesthesia discusses the origin of the loss of consciousness during anaesthesia.

Localization of brain 5α-reductase messenger RNA in mice selectively bred for high chronic alcohol withdrawal severity

Several lines of evidence suggest that fluctuations in endogenous levels of the γ-aminobutyric acid (GABA)ergic neurosteroid allopregnanolone (ALLO) represent one mechanism for regulation of GABAergic inhibitory tone in the brain, with an ultimate impact on behavior. Consistent with this idea, there was an inverse relationship between ALLO levels and symptoms of anxiety and depression in humans and convulsive activity in rodents during alcohol withdrawal. Our recent studies examined the activity and expression of 5α-reductase ( Srd5a1), the rate-limiting enzyme in the biosynthesis of ALLO, during alcohol withdrawal in mice selectively bred for high chronic alcohol withdrawal (Withdrawal Seizure-Prone [WSP]) and found that Srd5a1 was downregulated in the cortex and hippocampus over the time course of dependence and withdrawal. The purpose of the present studies was to extend these findings and more discretely map the regions of Srd5a1 expression in mouse brain using radioactive in situ hybridization in WSP mice that were ethanol naïve, following exposure to 72 h ethanol vapor (dependent) or during peak withdrawal. In naïve animals, expression of Srd5a1 was widely distributed throughout the mouse brain, with highest expression in specific regions of the cerebral cortex, hippocampus, thalamus, hypothalamus, and amygdala. In dependent animals and during withdrawal, there was no change in Srd5a1 expression in cortex or hippocampus, which differed from our recent findings in dissected tissues. These results suggest that local Srd5a1 mRNA expression in WSP brain may not change in parallel with local ALLO content or withdrawal severity.

ClC-2 contributes to tonic inhibition mediated by α5 subunit-containing GABAA receptor in experimental temporal lobe epilepsy

Temporal lobe epilepsy (TLE), characterized by spontaneous recurrent seizures, learning and memory impairments is associated with neurodegeneration, abnormal reorganization of the circuitry and loss of functional inhibition in hippocampus. In adult hippocampus, the GABAergic cells mediate the major inhibitory function of the principal neurons, promoting the Cl(-) entry through the GABA(A) receptor, whether through phasic (synaptic) or tonic (extrasynaptic) conductance. Aside from classical synaptic component, tonic GABAergic inhibition mediated by extrasynaptic GABA(A) receptor received increasing attention over the past years. There is growing evidence that tonic inhibition plays an important role in epilepsy, memory and cognition. Since GABA(A) receptor-mediated inhibition depends on the maintenance of intracellular Cl(-) concentration at low levels in mature neurons, a shift in E(cl) is likely to participate in the generation and not merely a consequence of TLE. As we know, chloride channel-2 (ClC-2) is a member of the supergene family of voltage-gated chloride channels, it constitutes part of the background conductance and is involved in chloride extrusion. Here we show that ClC-2 were upregulated functionally in CA1 pyramidal cells in pilocarpine-treated rats, and that an observed increase in ClC-2 currents in CA1 pyramidal cells was reversed by L655,708, a specific antagonist of α5 subunit-containing GABA(A) receptor.

Altered GABA transmission in a mouse model of increased trait anxiety

Anxiety disorders are the most prevalent central nervous system diseases imposing a high social burden to our society. Emotional processing is particularly controlled by GABA-ergic transmission in the amygdala. Using in situ hybridization and immunohistochemistry we now investigated changes in the expression of GABA synthesizing enzymes (GAD65 and GAD67), GABAA (α1–5, β1–3, γ1–2) and GABAB receptor subunits (GBBR1, GBBR2) in amygdaloid nuclei of high anxiety-related behavior (HAB) mice in comparison to mice selected for normal anxiety-related behavior (NAB). Levels of GAD65 and GAD67 mRNAs and protein, as well as those of GABA were increased in the amygdala of HAB mice. Relative to NAB controls, mRNA expression of the GABAA receptor subunits β1, β2 and γ2 was specifically increased in the basolateral amygdala of HAB mice while transcription of α5 and γ1 subunits was reduced in the central and medial amygdala. On the protein level, increases in β2 and γ2 subunit immunoreactivities were evident in the basolateral amygdala of HAB mice. No change in GABAB receptor expression was observed. These findings point towards an imbalanced GABA-ergic neurotransmission in the amygdala of HAB mice. On the other hand, FosB, a marker for neuronal activity, was increased in principal neurons of the basolateral amygdala in HAB mice, reflecting activation of excitatory neurons, possibly as a consequence of reduced GABA-ergic tonic inhibition through α5 and γ1 containing receptors. Ultimately these mechanisms may lead to the compensatory activation of GABA transmission, as indicated by the increased expression of GAD65/67 in HAB mice.

Modulation of Oscillatory Synchronization in an Interneuronal Network under the Influence of Tonic GABA-ergic Inhibition: a Model Study

The influence of a tonic GABA-ergic current on the processes of network synchronization was examined using a computer model of the neural network with shunting GABA-ergic synapses and tonic excitation that initiated spiking. The tonic inhibitory current was characterized by two parameters, the reversal potential and the conductance introduced. We found that tonic current with a reversal potential more negative than the threshold for spike generation reduces the network spiking frequency and synchronization. A monotonic decrease in the network synchronization with augmentation of the tonic current conductance was shown. We also found that a particular range of tonic current conductance leads to a bistable character of the network dynamics. Depending on the initial conditions of the network examined, spontaneous synchronous oscillations similar to epileptiform activity could appear.

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). The type A GABA receptor (GABA(A)R) system is the primary pharmacological target for many drugs used in clinical anesthesia. The α1, β2, and γ2 subunit-containing GABA(A)Rs located in the various parts of CNS are thought to be involved in versatile effects caused by inhaled anesthetics and classic benzodiazepines (BZD), both of which are widely used in clinical anesthesiology. During the past decade, the emergence of tonic inhibitory conductance in extrasynaptic GABA(A)Rs has coincided with evidence showing that these receptors are highly sensitive to the sedatives and hypnotics used in anesthesia. Anesthetic enhancement of tonic GABAergic inhibition seems to be preferentially increased in regions shown to be important in controlling memory, awareness, and sleep. This review focuses on the physiology of the GABA(A)Rs and the pharmacological properties of clinically used BZDs. Although classic BZDs are widely used in anesthesiological practice, there is a constant need for new drugs with more favorable pharmacokinetic and pharmacodynamic effects and fewer side effects. New hypnotics are currently developed, and promising results for one of these, the GABA(A)R agonist remimazolam, have recently been published.

Sex-specificity of associative learning-induced changes in GABAergic tonic inhibition in layer 4 neurons of mouse barrel cortex

We show that in naïve mice, tonic currents mediated by δ subunit-containing GABA A receptors in fast spiking interneurons are larger in females than in males while in regular spiking neurons such a difference was not observed. Moreover, in fast spiking interneurons, associative learning induced a larger reduction of these currents in females than in males. In contrast, in regular spiking neurons, learning similarly enhanced tonic currents in both sexes.

Neurosteroid modulation of arterial baroreflex function in the rostral ventrolateral medulla

Through both genomic and nongenomic actions, ovarian hormones and their metabolites have significant effects on the central nervous system to modulate a variety of regulatory systems, including the cardiovascular system. The major metabolite of progesterone, 3α-hydroxy-dihydroprogesterone, is the most potent endogenous positive modulator of GABA A receptors known and central nervous system levels of this progesterone metabolite fluctuate with the ovarian cycle and are elevated in pregnant animals. Pregnancy is associated with attenuated arterial baroreflex sympathoexcitation and increased tonic GABAergic inhibition of the rostral ventrolateral medulla (RVLM) likely contributes. The current experiments were performed to determine if the effects of pregnancy on arterial baroreflex control of renal sympathetic nerve activity could be mimicked by microinjection of the neuroactive progesterone metabolite into the RVLM. Compared to control values, 15 min after microinjection of 3α-hydroxy-dihydroprogesterone into the RVLM ( n = 10), baseline renal sympathetic nerve activity was decreased to 82% of baseline, and the range (157 ± 10 to 131 ± 11%) and maximum nerve activity (164 ± 9 to 136 ± 12%) for the arterial baroreflex curves were decreased. In contrast, microinjection of the inactive isomer, 3β-hydroxy-dihydroprogesterone into the RVLM ( n = 9), had no effect on baseline nerve activity or the arterial baroreflex nerve activity range or maximum. Thus, although multiple mechanisms likely contribute to pregnancy associated changes in baroreflex function, these experiments suggest that increased levels of 3α-hydroxy-dihydroprogesterone in the RVLM might contribute.