CiteULike: Tag gaba

Heterosynaptic LTD of Hippocampal GABAergic Synapses: A Novel Role of Endocannabinoids in Regulating Excitability

Vivien Chevaleyre — 2007-10-02T14:36:46-00:00

Neuron, Vol. 38, No. 3. (8 May 2003), pp. 461-472.

Neuronal excitability and long-term synaptic plasticity at excitatory synapses are critically dependent on the level of inhibition, and accordingly, changes of inhibitory synaptic efficacy should have great impact on neuronal function and neural network processing. We describe here a form of activity-dependent long-term depression at hippocampal inhibitory synapses that is triggered postsynaptically via glutamate receptor activation but is expressed presynaptically. That is, glutamate released by repetitive activation of Schaffer collaterals activates group I metabotropic glutamate receptors at CA1 pyramidal cells, triggering a persistent reduction of GABA release that is mediated by endocannabinoids. This heterosynaptic form of plasticity is involved in changes of pyramidal cell excitability associated with long-term potentiation at excitatory synapses and could account for the effects of cannabinoids on learning and memory.

Endocannabinoids: Getting the message across

Bradley Alger — 2007-05-04T23:25:13-00:00

PNAS, Vol. 101, No. 23. (8 June 2004), pp. 8512-8513.

10.1073/pnas.0402935101

Role of Endogenous Cannabinoids in Synaptic Signaling

Tamas Freund — 2007-05-05T00:05:26-00:00

Physiol. Rev., Vol. 83, No. 3. (1 July 2003), pp. 1017-1066.

Freund, Tamas F., Istvan Katona, and Daniele Piomelli. Role of Endogenous Cannabinoids in Synaptic Signaling. Physiol Rev 83: 1017-1066, 2003; 10.1152/physrev.00004.2003.--Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimimetic activity (endocannabinoids) and the cloning of their molecular targets, the CB1 and CB2 receptors. Although the existence of an endogenous cannabinoid signaling system has been established for a decade, its physiological roles have just begun to unfold. In addition, the behavioral effects of exogenous cannabinoids such as delta-9-tetrahydrocannabinol, the major active compound of hashish and marijuana, await explanation at the cellular and network levels. Recent physiological, pharmacological, and high-resolution anatomical studies provided evidence that the major physiological effect of cannabinoids is the regulation of neurotransmitter release via activation of presynaptic CB1 receptors located on distinct types of axon terminals throughout the brain. Subsequent discoveries shed light on the functional consequences of this localization by demonstrating the involvement of endocannabinoids in retrograde signaling at GABAergic and glutamatergic synapses. In this review, we aim to synthesize recent progress in our understanding of the physiological roles of endocannabinoids in the brain. First, the synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation. The fine-grain anatomical distribution of the neuronal cannabinoid receptor CB1 is described in most brain areas, emphasizing its general presynaptic localization and role in controlling neurotransmitter release. Finally, the possible functions of endocannabinoids as retrograde synaptic signal molecules are discussed in relation to synaptic plasticity and network activity patterns. 10.1152/physrev.00004.2003

Common structural requirements for heptahelical domain function in class A and class C GPCRS.

Virginie Binet — 2007-02-26T09:20:42-00:00

J Biol Chem (19 February 2007)

G protein-coupled receptors (GPCRs) are key players in cell communication. Several classes of such receptors have been identified. Although all GPCRs possess a heptahelical domain directly activating G proteins, important structural and sequence differences within receptors from different classes suggested distinct activation mechanisms. Here we show that highly conserved charged residues likely involved in an interaction network between transmembrane domains (TM) 3 and 6 at the cytoplasmic side of class C GPCRs are critical for activation of the GABAB receptor. Indeed, the loss of function resulting from the mutation of the conserved lysine residue into aspartate or glutamate in the TM3 of GABAB2 can be partly rescued by mutating the conserved acidic residue of TM6 into either lysine or arginine. In addition, mutation of the conserved lysine into an acidic residue leads to a non-functionnal receptor that displays a high agonist affinity. This is reminiscent to a similar ionic network that constitutes a lock stabilizing the inactive state of many class A rhodopsin-like GPCRs. These data reveal that despite their original structure class C GPCRs share with class A receptors at least some common structural feature controlling G-protein activation.

Modulation of human corticomotor excitability by somatosensory input.

A Kaelin-Lang — 2005-10-26T13:03:38-00:00

J Physiol, Vol. 540, No. Pt 2. (15 April 2002), pp. 623-633.

In humans, somatosensory stimulation results in increased corticomotoneuronal excitability to the stimulated body parts. The purpose of this study was to investigate the underlying mechanisms. We recorded motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) from abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) muscles. MEP amplitudes, recruitment curves (RC), intracortical inhibition (ICI), intracortical facilitation (ICF), resting (rMT) and active motor thresholds (aMT) were recorded before and after a 2-h period of ulnar nerve electrical stimulation at the wrist. Somatosensory input was monitored by recording somatosensory evoked potentials. To differentiate excitability changes at cortical vs. subcortical sites, we recorded supramaximal peripheral M-responses and MEPs to brainstem electrical stimulation (BES). In order to investigate the involvement of GABAergic mechanisms, we studied the influence of lorazepam (LZ) (a GABA(A) receptor agonist) relative to that of dextromethorphan (DM) (an NMDA receptor antagonist) and placebo in a double-blind design. We found that somatosensory stimulation increased MEP amplitudes to TMS only in the ADM, confirming a previous report. This effect was blocked by LZ but not by either DM or placebo and lasted between 8 and 20 min in the absence of (i) changes in MEPs elicited by BES, (ii) amplitudes of early somatosensory-evoked potentials or (iii) M-responses. We conclude that somatosensory stimulation elicited a focal increase in corticomotoneuronal excitability that outlasts the stimulation period and probably occurs at cortical sites. The antagonistic effect of LZ supports the hypothesis of GABAergic involvement as an operating mechanism.

Cholinergic modulation of nucleus accumbens medium spiny neurons.

M de Rover — 2008-01-09T21:42:25-00:00

Eur J Neurosci, Vol. 16, No. 12. (December 2002), pp. 2279-2290.

The rat nucleus accumbens contains acetylcholine-releasing interneurons, presumed to play a regulatory role in the electrical activity of medium spiny output neurons. In order to examine this issue in detail, we made electrophysiological recordings in rat nucleus accumbens slices. These experiments showed that gamma-aminobutyric acid-mediated inhibition of the output neurons might be facilitated by activation of nicotinic acetylcholine receptors, in addition to being suppressed via activation of muscarinic acetylcholine receptors. In contrast, glutamatergic excitation of output neurons appeared to be inhibited by activation of muscarinic acetylcholine receptors and to be insensitive to activation of nicotinic acetylcholine receptors. The spontaneous firing frequency of cholinergic neurons appeared to be under control of both a muscarinic and a nicotinic pathway in a bi-directional manner. Finally, we made paired recordings in which the functional connection between cholinergic neurons and output neurons was monitored. Driving the cholinergic neurons at physiological firing frequencies stimulated gamma-aminobutyric acid-mediated inhibition of the output neurons, via activation of nicotinic acetylcholine receptors. The onset of this effect was slow and lacked a fixed delay. These data indicate that activation of nicotinic acetylcholine receptors in rat nucleus accumbens may mediate the facilitation of gamma-aminobutyric acid-mediated inhibition of medium spiny output neurons. Possible mechanisms of neurotransmission, mediating this cholinergic modulation are discussed.

Developmental Modulation of GABAA Receptor Function by RNA Editing

Elizabeth Rula — 2008-06-11T18:55:44-00:00

J. Neurosci., Vol. 28, No. 24. (11 June 2008), pp. 6196-6201.

Adenosine-to-inosine (A-to-I) editing of RNA transcripts is an increasingly recognized cellular strategy to modulate the function of proteins involved in neuronal excitability. We have characterized the editing of transcripts encoding the alpha3 subunit of heteromeric GABAA receptors (Gabra3), in which a genomically encoded isoleucine codon (ATA) is converted to a methionine codon (ATI) in a region encoding the predicted third transmembrane domain of this subunit. Editing at this position (I/M site) was regulated in a spatiotemporal manner with [~]90% of the Gabra3 transcripts edited in most regions of adult mouse brain, but with lower levels of editing in the hippocampus. Editing was low in whole-mouse brain at embryonic day 15 and increased during development, reaching maximal levels by postnatal day 7. GABA-evoked current in transfected cells expressing nonedited alpha3(I)3gamma2L GABAA receptors activated more rapidly and deactivated much more slowly than edited alpha3(M)3gamma2L receptors. Furthermore, currents from nonedited alpha3(I)3gamma2L receptors were strongly outwardly rectifying (corresponding to chloride ion influx), whereas currents from edited alpha3(M)3gamma2L receptors had a more linear current/voltage relationship. These studies suggest that increased expression of the nonedited alpha3(I) subunit during brain development, when GABA is depolarizing, may allow the robust excitatory responses that are critical for normal synapse formation. However, the strong chloride ion influx conducted by receptors containing the nonedited alpha3(I) subunit could act as a shunt to prevent excessive excitation, providing the delicate balance necessary for normal neuronal development. 10.1523/JNEUROSCI.0443-08.2008

Impaired GABAergic transmission disrupts normal homeostatic plasticity in rat cortical networks

Le Roux — 2008-06-20T21:21:44-00:00

European Journal of Neuroscience, Vol. 27, No. 12. (June 2008), pp. 3244-3256.

Subunit-Specific Trafficking of GABAA Receptors during Status Epilepticus

Howard Goodkin — 2008-03-05T18:45:24-00:00

J. Neurosci., Vol. 28, No. 10. (5 March 2008), pp. 2527-2538.

It is proposed that a reduced surface expression of GABAA receptors (GABARs) contributes to the pathogenesis of status epilepticus (SE), a condition characterized by prolonged seizures. This hypothesis was based on the finding that prolonged epileptiform bursting (repetitive bursts of prolonged depolarizations with superimposed action potentials) in cultures of dissociated hippocampal pyramidal neurons (dissociated cultures) results in the increased intracellular accumulation of GABARs. However, it is not known whether this rapid modification in the surface-expressed GABAR pool results from selective, subunit-dependent or nonselective, subunit-independent internalization of GABARs. In hippocampal slices obtained from animals undergoing prolonged SE (SE-treated slices), we found that the surface expression of the GABAR 2/3 and gamma2 subunits was reduced, whereas that of the delta subunit was not. Complementary electrophysiological recordings from dentate granule cells in SE-treated slices demonstrated a reduction in GABAR-mediated synaptic inhibition, but not tonic inhibition. A reduction in the surface expression of the gamma2 subunit, but not the delta subunit was also observed in dissociated cultures and organotypic hippocampal slice cultures when incubated in an elevated KCl external medium or an elevated KCl external medium supplemented with NMDA, respectively. Additional studies demonstrated that the reduction in the surface expression of the gamma2 subunit was independent of direct ligand binding of the GABAR. These findings demonstrate that the regulation of surface-expressed GABAR pool during SE is subunit-specific and occurs independent of ligand binding. The differential modulation of the surface expression of GABARs during SE has potential implications for the treatment of this neurological emergency. 10.1523/JNEUROSCI.3426-07.2008

LTP of GABAergic synapses in the ventral tegmental area and beyond

Fereshteh Nugent — 2008-03-17T18:35:23-00:00

J Physiol, Vol. 586, No. 6. (15 March 2008), pp. 1487-1493.

One of the mechanisms by which the experience-dependent reorganization of neural circuitry can occur is through changes in synaptic strength. Almost every excitatory synapse in the mammalian brain exhibits LTP (long-term potentiation) or LTD (long-term depression), two cellular mechanisms of synaptic plasticity. However, LTP and LTD have been reported much more rarely at fast inhibitory GABAA receptor synapses. Our recent study suggests that in vivo morphine initiates a long-lasting alteration of GABAergic synapses in the ventral tegmental area (VTA) by blocking the mechanisms required for LTP of GABAergic synapses. Here we put this work into the context of other examples of synaptic plasticity at GABAergic synapses. 10.1113/jphysiol.2007.148098

Posttraumatic GABAA-Mediated [Ca2+]i Increase Is Essential for the Induction of Brain-Derived Neurotrophic Factor-Dependent Survival of Mature Central Neurons

Anastasia Shulga — 2008-07-07T11:39:07-00:00

J. Neurosci., Vol. 28, No. 27. (2 July 2008), pp. 6996-7005.

A shift of GABAA-mediated responses from hyperpolarizing to depolarizing after neuronal injury leads to GABAA-mediated increase in [Ca2+]i. In addition, central neurons become dependent on BDNF for survival. Whether these two mechanisms are causally interrelated is an open question. Here, we show in lesioned CA3 hippocampal neurons in vitro and in axotomized corticospinal neurons in vivo that posttraumatic downregulation of the neuron-specific K-Cl cotransporter KCC2 leads to intracellular chloride accumulation by the Na-K-2Cl cotransporter NKCC1, resulting in GABA-induced [Ca2+]i transients. This mechanism is required by a population of neurons to survive in a BDNF-dependent manner after injury, because blocking GABAA-depolarization with the NKCC1 inhibitor bumetanide prevents the loss of neurons on BDNF withdrawal. The resurgence of KCC2 expression during recovery coincides with loss of BDNF dependency for survival. This is likely mediated through BDNF itself, because injured neurons reverse their response to this neurotrophin by switching the BDNF-induced downregulation of KCC2 to upregulation. 10.1523/JNEUROSCI.5268-07.2008

D1-Like Dopamine Receptor Activation Modulates GABAergic Inhibition But Not Electrical Coupling between Neocortical Fast-Spiking Interneurons

Stephen Towers — 2008-03-06T14:18:15-00:00

J. Neurosci., Vol. 28, No. 10. (5 March 2008), pp. 2633-2641.

Dopamine, acting through D1 receptors, is thought to play an important role in cognitive functions of the frontal cortex such as working memory. D1 receptors are widely expressed in fast-spiking (FS) interneurons, a prominent class of inhibitory cells that exert a powerful control of neuronal firing through proximal synapses on their postsynaptic targets. FS cells are extensively mutually interconnected by both GABAA receptor-mediated synapses and gap junction-mediated electrical synapses, and networks of FS cells play a crucial role in the generation of rhythmic synchronous activity. Although recent studies have documented the effects of dopamine modulation of neocortical synaptic connections among excitatory cells and between excitatory and various inhibitory cells, the effects of dopamine receptor activation on GABAergic and electrical interactions among FS cells is not known. To resolve this, we recorded from pairs of FS cells in the infragranular layers of mouse neocortical slices and tested the effects of D1-like (D1/D5) receptor activation on these connections. We found that D1-like receptor activation modulated GABAergic but not electrical connections between them. A D1-like receptor agonist preserved the strength of electrical coupling but reduced the amplitude of IPSPs and IPSCs between FS cells. Our results suggest that D1-like receptor activation has synapse-specific effects within networks of FS cells, with potential implications for the generation of rhythmic activity in the neocortex. 10.1523/JNEUROSCI.5079-07.2008

Activity-dependent PSA expression regulates inhibitory maturation and onset of critical period plasticity

Graziella Di Cristo — 2007-11-27T17:36:53-00:00

Nature Neuroscience, Vol. 10, No. 12. (18 November 2007), pp. 1569-1577.

Interplay between neuromodulator-induced switching of short-term plasticity at sensorimotor synapses in the neonatal rat spinal cord

Barriere — 2008-04-03T18:15:18-00:00

The Journal of Physiology, Vol. 586, No. 7. (April 2008), pp. 1903-1920.

Postsynaptic GABAB receptor signalling enhances LTD in mouse cerebellar Purkinje cells

Kamikubo — 2007-12-04T02:37:20-00:00

The Journal of Physiology, Vol. 585, No. 2. (December 2007), pp. 549-563.

Thermodynamic Regulation of NKCC1-Mediated Cl- Cotransport Underlies Plasticity of GABAA Signaling in Neonatal Neurons

Audrey Brumback — 2008-02-18T18:05:04-00:00

J. Neurosci., Vol. 28, No. 6. (6 February 2008), pp. 1301-1312.

In the adult brain, chloride (Cl) influx through GABAA receptors is an important mechanism of synaptic inhibition. However, under a variety of circumstances, including acquired epilepsy, neuropathic pain, after trains of action potentials or trauma, and during normal early brain development, GABAA receptor activation excites neurons by gating Cl efflux because the intracellular Cl concentration (Cli) is elevated. These findings require an inducible, active mechanism of chloride accumulation. We used gramicidin-perforated patch recordings to characterize Cl transport via NKCC1, the principal neuronal Cl accumulator, in neonatal CA1 pyramidal neurons. NKCC1 activity was required to maintain elevated Cli such that GABAA receptor activation was depolarizing. Kinetic analysis of NKCC1 revealed reversible transmembrane Cl transport characterized by a large maximum velocity (vmax) and high affinity (Km), so that NKCC1 transport was limited only by the net electrochemical driving force for Na+, K+, and Cl. At the steady-state Cli, NKCC1 was at thermodynamic equilibrium, and there was no evidence of net Cl transport. Trains of action potentials that have been previously shown to induce persistent changes in neuronal ECl (reversal potential for Cl) did not alter vmax or Km of NKCC1. Rather, action potentials shifted the thermodynamic set point, the steady-state Cli at which there was no net NKCC1-mediated Cl transport. The persistent increase in Cli required intact alpha2/alpha3 Na+-K+-ATPase activity, indicating that trains of action potentials reset the thermodynamic equilibrium for NKCC1 transport by lowering Nai. Activity-induced changes in Na+-K+-ATPase activity comprise a novel mechanism for persistent alterations in synaptic signaling mediated by GABA. 10.1523/JNEUROSCI.3378-07.2008

Dissociated Gender-Specific Effects of Recurrent Seizures on GABA Signaling in CA1 Pyramidal Neurons: Role of GABAA Receptors

Aristea Galanopoulou — 2008-02-18T18:01:17-00:00

J. Neurosci., Vol. 28, No. 7. (13 February 2008), pp. 1557-1567.

Early in development, the depolarizing GABAAergic signaling is needed for normal neuronal differentiation. It is shown here that hyperpolarizing reversal potentials of GABAAergic postsynaptic currents (EGABA) appear earlier in female than in male rat CA1 pyramidal neurons because of increased potassium chloride cotransporter 2 (KCC2) expression and decreased bumetanide-sensitive chloride transport in females. Three episodes of neonatal kainic acid-induced status epilepticus (3KA-SE), each elicited at postnatal days 4 (P4)P6, reverse the direction of GABAAergic responses in both sexes. In males, 3KA-SE trigger a premature appearance of hyperpolarizing GABAAergic signaling at P9, instead of P14. This is driven by an increase in KCC2 expression and decrease in bumetanide-sensitive chloride cotransport. In 3KA-SE females, EGABA transiently becomes depolarizing at P8P13 because of increase in the activity of a bumetanide-sensitive NKCC1 (sodium potassium chloride cotransporter 1)-like chloride cotransporter. However, females regain their hyperpolarizing GABAAergic signaling at P14 and do not manifest spontaneous seizures in adulthood. In maternally separated stressed controls, a hyperpolarizing shift in EGABA was observed in both sexes, associated with decreased bumetanide-sensitive chloride cotransport, whereas KCC2 immunoreactivity was increased in males only. GABAA receptor blockade at the time of 3KA-SE or maternal separation reversed their effects on EGABA. These data suggest that the direction of GABAA-receptor signaling may be a determining factor for the age and sex-specific effects of prolonged seizures in the hippocampus, because they relate to normal brain development and possibly epileptogenesis. These effects differ from the consequences of severe stress. 10.1523/JNEUROSCI.5180-07.2008

Altered synaptic and non-synaptic properties of CA1 pyramidal neurons in Kv4.2 knockout mice

BK Andrasfalvy — 2008-08-19T08:26:45-00:00

J Physiol, Vol. 586, No. 16. (15 August 2008), pp. 3881-3892.

Back-propagating action potentials (bAPs) travelling from the soma to the dendrites of neurons are involved in various aspects of synaptic plasticity. The distance-dependent increase in Kv4.2-mediated A-type K+ current along the apical dendrites of CA1 pyramidal cells (CA1 PCs) is responsible for the attenuation of bAP amplitude with distance from the soma. Genetic deletion of Kv4.2 reduced dendritic A-type K+ current and increased the bAP amplitude in distal dendrites. Our previous studies revealed that the amplitude of unitary Schaffer collateral inputs increases with distance from the soma along the apical dendrites of CA1 PCs. We tested the hypothesis that the weight of distal synapses is dependent on dendritic Kv4.2 channels. We compared the amplitude and kinetics of mEPSCs at different locations on the main apical trunk of CA1 PCs from wild-type (WT) and Kv4.2 knockout (KO) mice. While wild-type mice showed normal distance-dependent scaling, it was missing in the Kv4.2 KO mice. We also tested whether there was an increase in inhibition in the Kv4.2 knockout, induced in an attempt to compensate for a non-specific increase in neuronal excitability (after-polarization duration and burst firing probability were increased in KO). Indeed, we found that the magnitude of the tonic GABA current increased in Kv4.2 KO mice by 53% and the amplitude of mIPSCs increased by 25%, as recorded at the soma. Our results suggest important roles for the dendritic K+ channels in distance-dependent adjustment of synaptic strength as well as a primary role for tonic inhibition in the regulation of global synaptic strength and membrane excitability. 10.1113/jphysiol.2008.154336

Chemokine Signaling Controls Intracortical Migration and Final Distribution of GABAergic Interneurons

Guillermina Lopez-Bendito — 2008-02-18T17:57:34-00:00

J. Neurosci., Vol. 28, No. 7. (13 February 2008), pp. 1613-1624.

Functioning of the cerebral cortex requires the coordinated assembly of circuits involving glutamatergic projection neurons and GABAergic interneurons. Although much is known about the migration of interneurons from the subpallium to the cortex, our understanding of the mechanisms controlling their precise integration within the cortex is still limited. Here, we have investigated in detail the behavior of GABAergic interneurons as they first enter the developing cortex by using time-lapse videomicroscopy, slice culture, and in utero experimental manipulations and analysis of mouse mutants. We found that interneurons actively avoid the cortical plate for a period of [~]48 h after reaching the pallium; during this time, interneurons disperse tangentially through the marginal and subventricular zones. Perturbation of CXCL12/CXCR4 signaling causes premature cortical plate invasion by cortical interneurons and, in the long term, disrupts their laminar and regional distribution. These results suggest that regulation of cortical plate invasion by GABAergic interneurons is a key event in cortical development, because it directly influences the coordinated formation of appropriate glutamatergic and GABAergic neuronal assemblies. 10.1523/JNEUROSCI.4651-07.2008

Neurogenic Role of the Depolarizing Chloride Gradient Revealed by Global Overexpression of KCC2 from the Onset of Development

Annie Reynolds — 2008-02-18T17:55:01-00:00

J. Neurosci., Vol. 28, No. 7. (13 February 2008), pp. 1588-1597.

GABA- and glycine-induced depolarization is thought to provide important developmental signals, but the role of the underlying chloride gradient has not been examined from the onset of development. We therefore overexpressed globally the potassiumchloride cotransporter 2 (KCC2) in newly fertilized zebrafish embryos to reverse the chloride gradient. This rendered glycine hyperpolarizing in all neurons, tested at the time that motor behaviors (but not native KCC2) first appear. KCC2 overexpression resulted in fewer mature spontaneously active spinal neurons, more immature silent neurons, and disrupted motor activity. We observed fewer motoneurons and interneurons, a reduction in the elaboration of axonal tracts, and smaller brains and spinal cords. However, we observed no increased apoptosis and a normal complement of sensory neurons, glia, and progenitors. These results suggest that chloride-mediated excitation plays a crucial role in promoting neurogenesis from the earliest stages of embryonic development. 10.1523/JNEUROSCI.3791-07.2008

Depolarization promotes GAD 65-mediated GABA synthesis by a post-translational mechanism in neural stem cell-derived neurons

Gakhar-Koppole — 2008-01-23T11:54:43-00:00

European Journal of Neuroscience, Vol. 27, No. 2. (January 2008), pp. 269-283.

Metabotropic Glutamate Receptor Type 5-Dependent Long-Term Potentiation of Excitatory Synapses on Fast-Spiking GABAergic Neurons in Mouse Visual Cortex

Abdolrahman Sarihi — 2008-02-04T12:52:38-00:00

J. Neurosci., Vol. 28, No. 5. (30 January 2008), pp. 1224-1235.

Long-term potentiation (LTP) of excitatory synapses on GABAergic neurons in layer II/III of visual cortical slices was examined in GAD67-GFP knock-in mice by whole-cell recordings of EPSPs evoked by layer IV stimulation. Theta burst stimulation (TBS) paired with postsynaptic depolarization induced LTP in 14 of 19 fast-spiking GABAergic (FS-GABA) neurons, whereas only in 6 of 17 non-FS GABAergic neurons. The mean magnitude of LTP in the former cell group was larger than that in the latter. The paired-pulse stimulation protocol and coefficient of variation analysis indicated that LTP of excitatory synapses on FS-GABA neurons may be postsynaptic in origin. Filling postsynaptic cells with a Ca2+-chelator blocked the induction of LTP, suggesting an involvement of postsynaptic Ca2+ rise. The developmental analysis of LTP indicated that almost the same magnitude of LTP was induced after postnatal day 17 to the young adulthood, suggesting no age dependence after eye opening. This form of LTP was dependent neither on NMDA receptors nor voltage-gated Ca2+ channels (L and T types). An antagonist for type 5 metabotropic glutamate receptors (mGluR5) blocked this form of LTP, whereas an antagonist for mGluR1 was not effective. An agonist for mGluR1/5 induced potentiation of EPSPs of FS-GABA neurons in concentration- and use-dependent manners. This potentiation and TBS-induced LTP occluded each other. Further pharmacological analyses suggested that this form of LTP at FS-GABA neurons is induced through an activation of mGluR5, which triggers Ca2+ release from internal stores via activations of phospholipase C and inositol triphosphate. 10.1523/JNEUROSCI.4928-07.2008

Regional Distribution of Cortical Interneurons and Development of Inhibitory Tone Are Regulated by Cxcl12/Cxcr4 Signaling

Guangnan Li — 2008-02-04T12:47:34-00:00

J. Neurosci., Vol. 28, No. 5. (30 January 2008), pp. 1085-1098.

Interneurons are born in subcortical germinative zones and tangentially migrate in multiple streams above and below the developing cortex, and then, at the appropriate developmental stage, migrate radially into the cortex. The factors that control the formation of and the timing of exit from the streams remain obscure; moreover, the rationale for this complicated developmental plan is unclear. We show that a chemokine, Cxcl12, is an attractant for interneurons during the stage of stream formation and tangential migration. Furthermore, the timing of exit from the migratory streams accompanies loss of responsiveness to Cxcl12 as an attractant. Mice with mutations in Cxcr4 have disorganized migratory streams and deletion of Cxcr4 after the streams have formed precipitates premature entry into the cortical plate. In addition, constitutive deletion of Cxcr4 specifically in interneurons alters the regional distribution of interneurons within the cortex and leads to interneuron laminar positioning defects in the postnatal cortex. To examine the role of interneuron distribution on the development of cortical circuitry, we generated mice with focal defects in interneuron distribution and studied the density of postnatal inhibitory innervation in areas with too many and too few interneurons. Interestingly, alterations in IPSC frequency and amplitude in areas with excess interneurons tend toward normalization of inhibitory tone, but in areas with reduced interneuron density this system fails. Thus, the processes controlling interneuron sorting, migration, regional distribution, and laminar positioning can have significant consequences for the development of cortical circuitry and may have important implications for a range of neurodevelopmental disorders. 10.1523/JNEUROSCI.4602-07.2008

Efficient Ca2+ buffering in fast-spiking basket cells of rat hippocampus.

Yexica Aponte — 2008-03-06T15:15:35-00:00

J Physiol (14 February 2008)

Fast-spiking parvalbumin-expressing basket cells (BCs) represent a major type of inhibitory interneuron in the hippocampus. These cells inhibit principal cells in a temporally precise manner and are involved in the generation of network oscillations. Although BCs show a unique expression profile of Ca2+ permeable receptors, Ca2+ binding proteins, and Ca2+-dependent signaling molecules, physiological Ca2+ signaling in these interneurons has not been investigated. To study action potential (AP)-induced dendritic Ca2+ influx and buffering, we combined whole-cell patch-clamp recordings with ratiometric Ca2+ imaging from the proximal apical dendrites of rigorously identified BCs in acute slices, using the high-affinity Ca2+ indicator fura-2 or the low-affinity dye fura-FF. Single APs evoked dendritic Ca2+ transients with small amplitude. Bursts of APs evoked Ca2+ transients with amplitudes that increased linearly with AP number. Analysis of Ca2+ transients under steady-state conditions with different fura-2 concentrations and during loading with 200 microM fura-2 indicated that the endogenous Ca2+-binding ratio was ~ 200 (kappaS = 202 +/- 26 for the loading experiments). The peak amplitude of the Ca2+ transients measured directly with 100 microM fura-FF was 39 nM AP-1. At ~23 degrees C, the decay time constant of the Ca2+ transients was 390 ms, corresponding to an extrusion rate of ~600 s-1. At 34 degrees C, the decay time constant was 203 ms and the corresponding extrusion rate was ~1100 s-1. At both temperatures, continuous theta-burst activity with 3 - 5 APs per theta cycle, as occurs in vivo during exploration, led to a moderate increase in the global Ca2+ concentration that was proportional to AP number, whereas more intense stimulation was required to reach micromolar Ca2+ concentrations and to shift Ca2+ signaling into a nonlinear regime. In conclusion, dentate gyrus BCs show a high endogenous Ca2+-binding ratio, a small AP-induced dendritic Ca2+ influx, and a relatively slow Ca2+ extrusion. These specific buffering properties of BCs will sharpen the time course of local Ca2+ signals, while prolonging the decay of global Ca2+ signals.

Electric Fields Due to Synaptic Currents Sharpen Excitatory Transmission

Sergiy Sylantyev — 2008-03-28T10:51:59-00:00

Science, Vol. 319, No. 5871. (28 March 2008), pp. 1845-1849.

The synaptic response waveform, which determines signal integration properties in the brain, depends on the spatiotemporal profile of neurotransmitter in the synaptic cleft. Here, we show that electrophoretic interactions between AMPA receptormediated excitatory currents and negatively charged glutamate molecules accelerate the clearance of glutamate from the synaptic cleft, speeding up synaptic responses. This phenomenon is reversed upon depolarization and diminished when intracleft electric fields are weakened through a decrease in the AMPA receptor density. In contrast, the kinetics of receptor-mediated currents evoked by direct application of glutamate are voltage-independent, as are synaptic currents mediated by the electrically neutral neurotransmitter GABA. Voltage-dependent temporal tuning of excitatory synaptic responses may thus contribute to signal integration in neural circuits. 10.1126/science.1154330

GABA Regulates Excitatory Synapse Formation in the Neocortex via NMDA Receptor Activation

Doris Wang — 2008-05-26T10:26:51-00:00

J. Neurosci., Vol. 28, No. 21. (21 May 2008), pp. 5547-5558.

The development of a balance between excitatory and inhibitory synapses is a critical process in the generation and maturation of functional circuits. Accumulating evidence suggests that neuronal activity plays an important role in achieving such a balance in the developing cortex, but the mechanism that regulates this process is unknown. During development, GABA, the primary inhibitory neurotransmitter in adults, excites neurons as a result of high expression of the Na+-K+-2Cl- cotransporter (NKCC1). Using NKCC1 RNA interference knockdown in vivo, we show that GABA-induced depolarization is necessary for proper excitatory synapse formation and dendritic development of newborn cortical neurons. Blocking NKCC1 with the diuretic bumetanide during development leads to similar persistent changes in cortical circuitry in the adult. Interestingly, expression of a voltage-independent NMDA receptor rescues the failure of NKCC1 knockdown neurons to develop excitatory AMPA transmission, indicating that GABA depolarization cooperates with NMDA receptor activation to regulate excitatory synapse formation. Our study identifies an essential role for GABA in the synaptic integration of newborn cortical neurons and suggests an activity-dependent mechanism for achieving the balance between excitation and inhibition in the developing cortex. 10.1523/JNEUROSCI.5599-07.2008

Excitatory Actions of GABA in the Suprachiasmatic Nucleus

Hee Choi — 2008-05-26T10:22:54-00:00

J. Neurosci., Vol. 28, No. 21. (21 May 2008), pp. 5450-5459.

Neurons in the suprachiasmatic nucleus (SCN) are responsible for the generation of circadian oscillations, and understanding how these neurons communicate to form a functional circuit is a critical issue. The neurotransmitter GABA and its receptors are widely expressed in the SCN where they mediate cell-to-cell communication. Previous studies have raised the possibility that GABA can function as an excitatory transmitter in adult SCN neurons during the day, but this work is controversial. In the present study, we first tested the hypothesis that GABA can evoke excitatory responses during certain phases of the daily cycle by broadly sampling how SCN neurons respond to GABA using extracellular single-unit recording and gramicidin-perforated-patch recording techniques. We found that, although GABA inhibits most SCN neurons, some level of GABA-mediated excitation was present in both dorsal and ventral regions of the SCN, regardless of the time of day. These GABA-evoked excitatory responses were most common during the night in the dorsal SCN region. The Na+-K+-2Cl- cotransporter (NKCC) inhibitor, bumetanide, prevented these excitatory responses. In individual neurons, the application of bumetanide was sufficient to change GABA-evoked excitation to inhibition. Calcium-imaging experiments also indicated that GABA-elicited calcium transients in SCN cells are highly dependent on the NKCC isoform 1 (NKCC1). Finally, Western blot analysis indicated that NKCC1 expression in the dorsal SCN is higher in the night. Together, this work indicates that GABA can play an excitatory role in communication between adult SCN neurons and that this excitation is critically dependent on NKCC1. 10.1523/JNEUROSCI.5750-07.2008

GABAergic depolarization of the axon initial segment in cortical principal neurons is caused by the Na-K-2Cl cotransporter NKCC1.

S Khirug — 2008-05-07T08:41:33-00:00

The Journal of neuroscience : the official journal of the Society for Neuroscience, Vol. 28, No. 18. (30 April 2008), pp. 4635-4639.

GABAergic terminals of axo-axonic cells (AACs) are exclusively located on the axon initial segment (AIS) of cortical principal neurons, and they are generally thought to exert a powerful inhibitory action. However, recent work (Szabadics et al., 2006) indicates that this input from AACs can be depolarizing and even excitatory. Here, we used local photolysis of caged GABA to measure reversal potentials (E(GABA)) of GABA(A) receptor-mediated currents and to estimate the local chloride concentration in the AIS compared with other cellular compartments in dentate granule cells and neocortical pyramidal neurons. We found a robust axo-somato-dendritic gradient in which the E(GABA) values from the AIS to the soma and dendrites become progressively more negative. Data from NKCC1(-/-) and bumetanide-exposed neurons indicated that the depolarizing E(GABA) at the AIS is set by chloride uptake mediated by the Na-K-2Cl cotransporter NKCC1. Our findings demonstrate that spatially distinct interneuronal inputs can induce postsynaptic voltage responses with different amplitudes and polarities as governed by the subcellular distributions of plasmalemmal chloride transporters.

Specific inhibitory synapses shift the balance from feedforward to feedback inhibition of hippocampal CA1 pyramidal cells

Elfant — 2008-01-08T11:47:11-00:00

European Journal of Neuroscience, Vol. 27, No. 1. (January 2008), pp. 104-113.

Transition to seizures in the isolated immature mouse hippocampus: a switch from dominant phasic inhibition to dominant phasic excitation

Derchansky — 2008-01-18T03:19:51-00:00

The Journal of Physiology, Vol. 586, No. 2. (January 2008), pp. 477-494.

Gephyrin: where do we stand, where do we go?

Jean-Marc Fritschy — 2008-04-23T13:04:35-00:00

Trends in Neurosciences, Vol. In Press, Corrected Proof

Gephyrin is a multifunctional protein responsible for molybdenum cofactor synthesis and the clustering of glycine and GABAA receptors at inhibitory synapses. Based on the structure of its two conserved domains, G and E, gephyrin is thought to form a hexagonal lattice serving as a scaffold for accessory proteins at postsynaptic sites. However, important aspects of gephyrin gene expression, protein structure and regulation, as well as the role of gephyrin in synapse formation and plasticity, remain poorly understood. Here we review the current state of knowledge about gephyrin, highlighting new research avenues based on a different structural model and a revised nomenclature for gephyrin splice variants. Unraveling the biology of gephyrin will further our understanding of glycinergic and GABAergic synapses in health and disease.

Glycinergic Transmission Shaped by the Corelease of GABA in a Mammalian Auditory Synapse

Tao Lu — 2008-04-19T04:14:44-00:00

Neuron, Vol. 57, No. 4. (28 February 2008), pp. 524-535.

Summary The firing pattern of neurons is shaped by the convergence of excitation and inhibition, each with finely tuned magnitude and duration. In an auditory brainstem nucleus, glycinergic inhibition features fast decay kinetics, the mechanism of which is unknown. By applying glycine to native or recombinant glycine receptors, we show that response decay times are accelerated by addition of GABA, a weak partial agonist of glycine receptors. Systematic variation in agonist exposure time revealed that fast synaptic time course may be achieved with submillisecond exposures to mixtures of glycine and GABA at physiological concentrations. Accordingly, presynaptic terminals generally contained both transmitters, and depleting terminals of GABA slowed glycinergic synaptic currents. Thus, coreleased GABA accelerates glycinergic transmission by acting directly on glycine receptors, narrowing the time window for effective inhibition. Packaging both weak and strong agonists in vesicles may be a general means by which presynaptic neurons regulate the duration of postsynaptic responses.

The glutamateGABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer

Bak — 2006-07-18T09:29:23-00:00

Journal of Neurochemistry, Vol. 98, No. 3. (August 2006), pp. 641-653.

Mice Lacking the 65 kDa Isoform of Glutamic Acid Decarboxylase (GAD65) Maintain Normal Levels of GAD67 and GABA in Their Brains but Are Susceptible to Seizures

Hideo Asada — 2008-04-19T14:47:38-00:00

Biochemical and Biophysical Research Communications, Vol. 229, No. 3. (24 December 1996), pp. 891-895.

The gene encoding of the 65 kDa isoform of the [gamma]-aminobutyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase (GAD), GAD65, was targeted in mice by homologous recombination. Viable GAD65 -/- mice were obtained with the expected mendelian frequency and displayed no gross morphological defects. Despite the complete loss of GAD65 mRNA and protein in a homozygous mutant, there was no difference in GABA content in the brains of GAD65 +/+, +/-, and -/- mice. As for the other 67 kDa isoform (GAD67), the levels of mRNA and protein were largely unchanged by the GAD65 mutation. General behavior, including locomotor activity and performance in the Morris water maze task, appeared normal, but seizures were more easily induced by picrotoxin and pentylenetetrazol: the latencies to seizures induced by picrotoxin were shorter and the dose of pentylenetetrazol required for induction of seizures was lower.

Colocalization of multiple GABA<SUB><FONT SIZE='-1'>A</FONT></SUB> receptor subtypes with gephyrin at postsynaptic sites

Marco Sassoè-Pognetto — 2008-04-20T06:01:25-00:00

The Journal of Comparative Neurology, Vol. 420, No. 4. (2000), pp. 481-498.

Clustering of gamma aminobutyric acid (GABA)A receptors to postsynaptic sites requires the presence of both the

Activity-dependent expression of GAD67 in the granule cells of the rat hippocampus

Mónica Ramírez — 2008-04-20T05:44:47-00:00

Brain Research, Vol. 917, No. 2. (2 November 2001), pp. 139-146.

In the normal granule cells of the dentate gyrus glutamate, GABA and glutamic acid decarboxylase (GAD67) coexist. After kindled seizures, this enzyme is transiently overexpressed and simultaneous glutamatergic and GABAergic transmission in the mossy fiber projection occurs. Since this dual transmission is also seen after acutely-induced seizures, we decided to study the relationship between the expression of GAD67 and the induction of simultaneous glutamatergic and GABAergic transmission by kindled or acutely induced seizures. We also explored whether kindling of the dentate gyrus in vitro, that does not induce epileptiform activity, could induce the expression of GAD67. We confirm that kindling epilepsy induces the expression of GAD67 in the dentate gyrus. Despite the emergence of GABAergic transmission in the mossy fiber projection after a single seizure, GAD67 expression in the dentate gyrus appeared similar to controls, however, in the mossy fibers an enhanced immunostaining was evident. Interestingly, kindling the dentate gyrus in vitro induces a marked GAD67 staining in the granule cells. Our results show that after the activity-dependent emergence of simultaneous glutamatergic and GABAergic transmission from the mossy fibers, GAD67 is expressed in the mossy fibers and, upon long-lasting enduring stimulation periods, also in the dentate gyrus. Thus, this phenomenon does not depend on the presence of epileptic activity, but rather, on increased excitatory input onto the dentate gyrus. This can represent a protective mechanism that can sustain GABA synthesis in an activity-dependent manner.

GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits.

JM Fritschy — 2006-03-11T15:34:42-00:00

J Comp Neurol, Vol. 359, No. 1. (14 August 1995), pp. 154-194.

GABAA-receptors display an extensive structural heterogeneity based on the differential assembly of a family of at least 15 subunits (alpha 1-6, beta 1-3, gamma 1-3, delta, rho 1-2) into distinct heteromeric receptor complexes. The subunit composition of receptor subtypes is expected to determine their physiological properties and pharmacological profiles, thereby contributing to flexibility in signal transduction and allosteric modulation. In heterologous expression systems, functional receptors require a combination of alpha-, beta-, and gamma-subunit variants, the gamma 2-subunit being essential to convey a classical benzodiazepine site to the receptor. The subunit composition and stoichiometry of native GABAA-receptor subtypes remain unknown. The aim of this study was to identify immunohistochemically the main subunit combinations expressed in the adult rat brain and to allocate them to identified neurons. The regional and cellular distribution of seven major subunits (alpha 1, alpha 2, alpha 3, alpha 5, beta 2,3, gamma 2, delta) was visualized by immunoperoxidase staining with subunit-specific antibodies (the beta 2- and beta 3-subunits were covisualized with the monoclonal antibody bd-17). Putative receptor subtypes were identified on the basis of colocalization of subunits within individual neurons, as analyzed by confocal laser microscopy in double- and triple-immunofluorescence staining experiments. The results reveal an extraordinary heterogeneity in the distribution of GABAA-receptor subunits, as evidenced by abrupt changes in immunoreactivity along well-defined cytoarchitectonic boundaries and by pronounced differences in the cellular distribution of subunits among various types of neurons. Thus, functionally and morphologically diverse neurons were characterized by a distinct GABAA-receptor subunit repertoire. The multiple staining experiments identified 12 subunit combinations in defined neurons. The most prevalent combination was the triplet alpha 1/beta 2,3/gamma 2, detected in numerous cell types throughout the brain. An additional subunit (alpha 2, alpha 3, or delta) sometimes was associated with this triplet, pointing to the existence of receptors containing four subunits. The triplets alpha 2/beta 2,3/gamma 2, alpha 3/beta 2,3/gamma 2, and alpha 5/beta 2,3/gamma 2 were also identified in discrete cell populations. The prevalence of these seven combinations suggest that they represent major GABAA-receptor subtypes. Five combinations also apparently lacked the beta 2,3-subunits, including one devoid of gamma 2-subunit (alpha 1/alpha 2/gamma 2, alpha 2/gamma 2, alpha 3/gamma 2, alpha 2/alpha 3/gamma 2, alpha 2/alpha 5/delta).(ABSTRACT TRUNCATED AT 400 WORDS)

Cannabis, Inhibitory Neurons, and the Progressive Course of Schizophrenia

R Freedman — 2008-04-27T22:16:02-00:00

American Journal of Psychiatry, Vol. 165, No. 4. (1 April 2008), pp. 416-419.

10.1176/appi.ajp.2008.08010147

GABA-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence

M Soyka — 2008-01-23T16:10:29-00:00

Journal of Psychiatric Research, Vol. 42, No. 3. (February 2008), pp. 184-191.

Gamma-aminobutyric acid (GABA) A receptors are believed to mediate some of the physiological and behavioral actions of ethanol. Recent studies have suggested that genetic variants of the GABA-A receptor alpha2 subunit gene (GABRA2) are associated with alcohol dependence. The aim of this study is to confirm and extend the role of GABRA2 haplotypes in the liability to alcohol dependence. 291 (231 male) treatment-seeking alcohol-dependent individuals and 295 (153 male) control subjects were enrolled into the study. Characteristics of alcohol dependence were obtained using the SSAGA (semi-structured assessment of the genetics of alcoholism, German Version). Genotyping of 10 SNPs across the GABRA2 gene was performed following previous reports and using PCR. One genetic variant was detected to significantly differ between alcohol-dependent subjects and controls. Two common 8 SNP haplotypes and their complementary alleles were identified containing this SNP and were present in 89.9% of controls and 93.4% of the alcohol-dependent individuals. One of the haplotypes (T-C-A-C-A-T-T-C) was significantly associated with alcohol dependence and characteristics of alcohol withdrawal and severity of alcohol dependence (delirium tremens, withdrawal seizures). These findings support and extend the three previous studies implicating a GABA-A receptor subunit as contributing to the genetic risk for alcohol dependence. Possible implications of these findings are discussed.

D1 receptors in prefrontal cells and circuits

PS Goldman-Rakic — 2008-06-29T01:38:16-00:00

Brain Research Reviews, Vol. 31, No. 2-3. (March 2000), pp. 295-301.

Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex

2008-06-23T17:47:21-00:00

Nat Rev Neurosci, Vol. 9, No. 7. (July 2008), pp. 557-568.

Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model.

XJ Wang — 2005-03-21T23:03:26-00:00

J Neurosci, Vol. 16, No. 20. (15 October 1996), pp. 6402-6413.

Fast neuronal oscillations (gamma, 20-80 Hz) have been observed in the neocortex and hippocampus during behavioral arousal. Using computer simulations, we investigated the hypothesis that such rhythmic activity can emerge in a random network of interconnected GABAergic fast-spiking interneurons. Specific conditions for the population synchronization, on properties of single cells and the circuit, were identified. These include the following: (1) that the amplitude of spike afterhyperpolarization be above the GABAA synaptic reversal potential; (2) that the ratio between the synaptic decay time constant and the oscillation period be sufficiently large; (3) that the effects of heterogeneities be modest because of a steep frequency-current relationship of fast-spiking neurons. Furthermore, using a population coherence measure, based on coincident firings of neural pairs, it is demonstrated that large-scale network synchronization requires a critical (minimal) average number of synaptic contacts per cell, which is not sensitive to the network size. By changing the GABAA synaptic maximal conductance, synaptic decay time constant, or the mean external excitatory drive to the network, the neuronal firing frequencies were gradually and monotonically varied. By contrast, the network synchronization was found to be high only within a frequency band coinciding with the gamma (20-80 Hz) range. We conclude that the GABAA synaptic transmission provides a suitable mechanism for synchronized gamma oscillations in a sparsely connected network of fast-spiking interneurons. In turn, the interneuronal network can presumably maintain subthreshold oscillations in principal cell populations and serve to synchronize discharges of spatially distributed neurons.

Conserved pattern of tangential neuronal migration during forebrain development.

C Métin — 2007-07-12T13:38:58-00:00

Development, Vol. 134, No. 15. (August 2007), pp. 2815-2827.

Origin, timing and direction of neuronal migration during brain development determine the distinct organization of adult structures. Changes in these processes might have driven the evolution of the forebrain in vertebrates. GABAergic neurons originate from the ganglionic eminence in mammals and migrate tangentially to the cortex. We are interested in differences and similarities in tangential migration patterns across corresponding telencephalic territories in mammals and reptiles. Using morphological criteria and expression patterns of Darpp-32, Tbr1, Nkx2.1 and Pax6 genes, we show in slice cultures of turtle embryos that early cohorts of tangentially migrating cells are released from the medial ganglionic eminence between stages 14 and 18. Additional populations migrate tangentially from the dorsal subpallium. Large cohorts of tangentially migrating neurons originate ventral to the dorsal ventricular ridge at stage 14 and from the lateral ganglionic eminence from stage 15. Release of GABAergic cells from these regions was investigated further in explant cultures. Tangential migration in turtle proceeds in a fashion similar to mammals. In chimeric slice culture and in ovo graft experiments, the tangentially migrating cells behaved according to the host environment - turtle cells responded to the available cues in mouse slices and mouse cells assumed characteristic migratory routes in turtle brains, indicating highly conserved embryonic signals between these distant species. Our study contributes to the evaluation of theories on the origin of the dorsal cortex and indicates that tangential migration is universal in mammals and sauropsids.

Temazepam Triggers the Release of Vasopressin into the Rat Hypothalamic Paraventricular Nucleus: Novel Insight into Benzodiazepine Action on Hypothalamic–Pituitary–Adrenocortical System Activity During Stress

Tobias Welt — 2006-07-21T19:07:14-00:00

Neuropsychopharmacology, Vol. aop, No. current.

Extrasynaptic GABA(A) receptors in the crosshairs of hormones and ethanol.

Istvan Mody — 2007-08-24T16:02:25-00:00

Neurochem Int (17 July 2007)

Gamma-aminobutyric acid (GABA) is the main chemical inhibitory neurotransmitter in the brain. In the central nervous system (CNS) it acts on two distinct types of receptor: an ion channel, i.e., an "ionotropic" receptor permeable to Cl(-) and HCO(3)(-) (GABA(A) receptors) and a G-protein coupled "metabotropic" receptor that is linked to various effector mechanisms (GABA(B) receptors). This review will summarize novel developments in the physiology and pharmacology of GABA(A) receptors (GABA(A)Rs), specifically those found outside synapses. The focus will be on a particular combination of GABA(A)R subunits sensitive to ovarian and adrenal cortical steroid hormone metabolites that are synthesized in the brain (neurosteroids) and to sobriety impairing concentrations of ethanol. These receptors may be the final common pathway for interactions between ethanol and ovarian and stress-related neurosteroids.

The neurosteroids dehydroepiandrosterone sulfate and pregnenolone sulfate inhibit the UNC-49 GABA receptor through a common set of residues.

Vernon D Twede — 2007-08-24T16:02:11-00:00

Mol Pharmacol (22 August 2007)

Neurosteroids are endogenous neuromodulators that bind and allosterically regulate GABAA receptors. Residues were recently identified in the first transmembrane domain (M1) of GABAA receptor subunits that are important for neurosteroid modulation. We are studying the inhibition of GABAA receptors by sulfated neurosteroids. One of these, pregnenolone sulfate (PS), depends on six identified M1 residues to inhibit the UNC-49 GABA receptor, a homomeric GABA receptor from Caenorhabditis elegans that is homologous to the mammalian GABAA receptor. Here, we investigate the inhibition of the UNC-49 GABA receptor by another sulfated neurosteroid, dehydroepiandrosterone sulfate (DHEAS). DHEAS is identical to PS except that it contains a carbonyl oxygen instead of an acetyl group at C17 on the steroid D ring. UNC-49 mutations that affect PS inhibition had broadly parallel effects on DHEAS, suggesting the two neurosteroids act through similar mechanisms. However certain M1 mutations affected DHEAS differently than PS. Considering that first, the D ring contains the only structural difference between PS and DHEAS, and second, the strongest chemical and steric effects of a mutation are likely to be felt in the local environment of the altered residues, this result implies that the steroid D ring may contact M1 near the mutated residues. This possibility is interesting because current models of neurosteroid interactions with GABAA receptors, based on pregnane steroids, suggest that the steroid A ring binds M1, while the D ring binds M4. Our findings suggest that there may be considerable diversity in the way different classes of neurosteroids interact with GABAA receptors.

Steroids, neuroactive steroids and neurosteroids in psychopathology.

BO Dubrovsky — 2007-08-20T21:22:33-00:00

Prog Neuropsychopharmacol Biol Psychiatry, Vol. 29, No. 2. (February 2005), pp. 169-192.

The term "neurosteroid" (NS) was introduced by Baulieu in 1981 to name a steroid hormone, dehydroepiandrosterone sulfate (DHEAS), that was found at high levels in the brain long after gonadectomy and adrenalectomy, and shown later to be synthetized by the brain. Later, androstenedione, pregnenolone and their sulfates and lipid derivatives as well as tetrahydrometabolites of progesterone (P) and deoxycorticosterone (DOC) were identified as neurosteroids. The term "neuroactive steroid" (NAS) refers to steroids which, independent of their origin, are capable of modifying neural activities. NASs bind and modulate different types of membrane receptors. The GABA and sigma receptor complexes have been the most extensively studied, while glycine-activated chloride channels, nicotinic acetylcholine receptors, voltage-activated calcium channels, although less explored, are also modulated by NASs. Within the glutamate receptor family, N-methyl-d-aspartate (NMDA) receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainate receptors have also been demonstrated to be a target for steroid modulation. Besides their membrane effects, once inside the neuron oxidation of Ring A reduced pregnanes, THP and THDOC, bind to the progesterone intracellular receptor and regulate gene expression through this path. The involvement of NASs on depression syndromes, anxiety disorders, stress responses to different stress stimuli, memory processes and related phenomena such as long-term potentiation are reviewed and critically evaluated. The importance of context for the interpretation of behavioral effects of hormones as well as for hormonal levels in body fluids is emphasized. Some suggestions for further research are given.

Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain.

RH Purdy — 2007-08-20T21:18:45-00:00

Proc Natl Acad Sci U S A, Vol. 88, No. 10. (15 May 1991), pp. 4553-4557.

A 3 alpha-hydroxy A-ring-reduced metabolite of progesterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone), and one of deoxycorticosterone (DOC), 3 alpha,21-dihydroxy-5 alpha-pregnan-20- one (allotetrahydroDOC), are among the most potent known ligands of gamma-aminobutyric acid (GABA) receptors designated GABAA in the central nervous system. With specific radioimmunoassays, rapid (less than 5 min) and robust (4- to 20-fold) increases of allopregnanolone and allotetrahydroDOC were detected in the brain (cerebral cortex and hypothalamus) and in plasma of rats after exposure to ambient temperature swin stress. Neither steroid was detectable in the plasma of adrenalectomized rats either before or after swim stress. However, allopregnanolone, but not allotetrahydroDOC, was still present in the cerebral cortex (greater than 3 ng/g) after adrenalectomy. These data demonstrate the presence of allopregnanolone and allotetrahydroDOC in brain and show that acute stress results in a rapid increase of these neuroactive steroids to levels known to modulate GABAA receptor function.

Auto-modulation of neuroactive steroids on GABA A receptors: a novel pharmacological effect.

F Wegner — 2007-08-22T16:12:39-00:00

Neuropharmacology, Vol. 52, No. 2. (February 2007), pp. 672-683.

GABA(A) receptor function is modulated by various important drugs including neuroactive steroids that act on allosteric modulatory sites and can directly activate GABA(A) receptor channels at high concentrations. We used whole cell patch-clamp recordings and rapid applications of the neuroactive steroid alphaxalone to investigate repetitive steroid effects. Alphaxalone potentiation of submaximal GABA-evoked currents was enhanced significantly by repetitive coapplications at all investigated recombinant isoforms (alpha1beta3delta, alpha1beta3gamma2L, alpha6beta3delta, alpha6beta3gamma2L) and at GABA(A) receptors of differentiated human NT2 neurons. A similar increase of current amplitudes was induced by repetitive applications of a high steroid concentration without GABA. We refer to these reversible effects as auto-modulation because repeated interactions of steroids enhanced their own pharmacological impact at the receptor sites in a time and concentration dependent manner without affecting GABA controls. Pronounced auto-modulatory actions were also measured using the neurosteroid 5alpha-THDOC in contrast to indiplon, THIP, and pentobarbital indicating a steroid specificity. Protein kinase A inhibition significantly reduced alphaxalone auto-modulation at alpha1beta3gamma2L, alpha6beta3gamma2L, and alpha6beta3delta subtypes while it enhanced potentiation at alpha1beta3delta isoforms suggesting a crucial influence of receptor subunit composition and phosphorylation for steroid actions. Especially at extrasynaptic GABA(A) receptor sites containing the delta subunit steroid auto-modulation may have a critical role in enhancing potentiation of GABA-induced currents.