Enhanced macroscopic desensitization shapes the response of ?4 subtype-containing GABA A receptors to synaptic and extrasynaptic GABA (original) (raw)
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Journal of neurophysiology, 1997
Cultured rat hippocampal neurons previously exposed to a media containing no added Mg2+ for 3 h begin to spontaneously trigger recurrent epileptiform discharges following return to normal medium, and this altered population epileptiform activity persisted for the life of the neurons in culture (> 2 wk). Neurons in "epileptic" cultures appeared similar in somatic and dendritic morphology and cellular density to control, untreated cultures. In patch-clamp recordings from hippocampal pyramidal cells from "epileptic," low Mg2+ pretreated hippocampal cultures, a rapid (within 2 h of treatment), permanent (lasting > or = 8 days) and statistically significant 50-65% reduction in the current density of functional gamma-aminobutyric acid-A (GABA(A)) receptors was evident when the GABA responses of these cells were compared with control neurons. Functional GABA receptor current density was calculated by determining the maximal response of a cell to GABA 1 mM applicat...
Proceedings of the National Academy of Sciences, 2007
A study was made of the ''rundown'' of GABAA receptors, microtransplanted to Xenopus oocytes from surgically resected brain tissues of patients afflicted with drug-resistant human mesial temporal lobe epilepsy (mTLE). Cell membranes, isolated from mTLE neocortex specimens, were injected into frog oocytes that rapidly incorporated functional GABA A receptors. Upon repetitive activation with GABA (1 mM), ''epileptic'' GABAA receptors exhibited a GABA A-current (IGABA) rundown that was significantly enhanced by Zn 2؉ (<250 M), and practically abolished by the high-affinity GABA A receptor inverse agonist SR95531 (gabazine; 2.5-25 M). Conversely, IGABA generated by ''control'' GABAA receptors microtransplanted from nonepileptic temporal lobe, lesional TLE, or authoptic disease-free tissues remained stable during repetitive stimulation, even in oocytes treated with Zn 2؉ . We conclude that rundown of mTLE epileptic receptors depends on the presence of ''phasic GABAA receptors'' that have low sensitivity to antagonism by Zn 2؉ . Additionally, we found that GABAA receptors, microtransplanted from the cerebral cortex of adult rats exhibiting recurrent seizures, caused by pilocarpine-induced status epilepticus, showed greater rundown than control tissue, an event also occurring in patch-clamped rat pyramidal neurons. Rundown of epileptic rat receptors resembled that of human mTLE receptors, being enhanced by Zn 2؉ (40 M) and sensitive to the antiepileptic agent levetiracetam, the neurotrophin brain-derived neurotrophic factor, and the phosphatase blocker okadaic acid. Our findings point to the rundown of GABA A receptors as a hallmark of TLE and suggest that modulating tonic and phasic mTLE GABA A receptor activity may represent a useful therapeutic approach to the disease.
GABAA-current rundown of temporal lobe epilepsy is associated with repetitive activation of GABAA
Proceedings of The National Academy of Sciences, 2007
A study was made of the ''rundown'' of GABAA receptors, microtransplanted to Xenopus oocytes from surgically resected brain tissues of patients afflicted with drug-resistant human mesial temporal lobe epilepsy (mTLE). Cell membranes, isolated from mTLE neocortex specimens, were injected into frog oocytes that rapidly incorporated functional GABA A receptors. Upon repetitive activation with GABA (1 mM), ''epileptic'' GABAA receptors exhibited a GABA A-current (IGABA) rundown that was significantly enhanced by Zn 2؉ (<250 M), and practically abolished by the high-affinity GABA A receptor inverse agonist SR95531 (gabazine; 2.5-25 M). Conversely, IGABA generated by ''control'' GABAA receptors microtransplanted from nonepileptic temporal lobe, lesional TLE, or authoptic disease-free tissues remained stable during repetitive stimulation, even in oocytes treated with Zn 2؉ . We conclude that rundown of mTLE epileptic receptors depends on the presence of ''phasic GABAA receptors'' that have low sensitivity to antagonism by Zn 2؉ . Additionally, we found that GABAA receptors, microtransplanted from the cerebral cortex of adult rats exhibiting recurrent seizures, caused by pilocarpine-induced status epilepticus, showed greater rundown than control tissue, an event also occurring in patch-clamped rat pyramidal neurons. Rundown of epileptic rat receptors resembled that of human mTLE receptors, being enhanced by Zn 2؉ (40 M) and sensitive to the antiepileptic agent levetiracetam, the neurotrophin brain-derived neurotrophic factor, and the phosphatase blocker okadaic acid. Our findings point to the rundown of GABA A receptors as a hallmark of TLE and suggest that modulating tonic and phasic mTLE GABA A receptor activity may represent a useful therapeutic approach to the disease.
European Journal of Neuroscience, 2007
Inhibitory postsynaptic currents (IPSCs) of the thalamic reticular (RT) nucleus are dramatically slower than in the neighboring ventrobasal (VB) neurons. It has been suggested that a3-subunit-containing receptors underlie slow IPSCs in RT neurons, while rapid synaptic currents in the VB nucleus are due to c-aminobutyric acid A receptors (GABA A Rs), including the a1-subunit. In our recent study Eur. J. Neurosci., 25, 2726J. Neurosci., 25, -2740 we have found that profound differences in kinetics of currents mediated by a3b2c2 and a1b2c3 receptors resulted from distinct binding and desensitization properties. However, a direct comparison between kinetics of neuronal GABA A Rs from RT and VB neurons and a3-and a1-subunit-containing receptors has not been made. For this purpose, current responses to ultrafast GABA applications were recorded from patches excised from neurons in VB and RT areas. Deactivation kinetics determined for RT and VB neurons closely resembled that in currents mediated by a3b2c2 and a1b2c2 receptors. In RT neurons, currents elicited by non-saturating [GABA] had a remarkably slow onset, a hallmark of a3subunit-containing receptors. In VB and RT neurons, single-channel currents elicited by brief GABA pulses had similar characteristics to those of a1b2c2 and a3b2c2 receptors. However, in stationary conditions, similarity between single-channel currents in neurons and respective recombinant receptors was less apparent. We propose that the non-stationary kinetics of GABAergic currents in VB and RT nuclei mimic that of currents mediated by a1-and a3-subunit-containing receptors. The dissimilarity between stationary kinetics of neuronal and recombinant receptors probably reflects differences between GABA A Rs mediating phasic and tonic currents in these neurons.
Saturation and self-inhibition of rat hippocampal GABAA receptors at high GABA concentrations
European Journal of Neuroscience, 2002
Current responses to ultrafast g-aminobutyric acid (GABA) applications were recorded from excised patches in rat hippocampal neurons to study the gating properties of GABA A receptors at GABA concentrations close to saturating ones and higher. The amplitude of currents saturated at approximately 1 mM, while the onset rate of responses reached saturation at 4±6 mM GABA. At high GABA concentrations (> 10 mM), the amplitude of current responses was reduced in a dose-dependent manner with a half-blocking GABA concentration of approximately 50 mM. The peak reduction at high GABA doses was accompanied by a tendency to increase the steady-state to peak ratio. At concentrations higher than 30 mM, this effect took the form of a rebound current, i.e. during the prolonged GABA applications, the current ®rstly declined due to desensitization onset and then, instead of decreasing towards a steady-state value, clearly increased. Both the self-inhibition of GABA A receptors by high GABA doses and rebound were clearly voltage dependent, being larger at positive holding potentials. The fast desensitization component accelerated with depolarization at all saturating [GABA] tested. The rebound phenomenon indicates that the self-block of GABA A receptors is state dependent, and suggests that the sojourn in the desensitized conformation provides a`rescue' from the block. We propose that high GABA concentrations inhibit the receptors by direct occlusion of the channel pore having no effect on the receptor gating.
Electrophysiology of GABA-mediated synaptic transmission and possible roles in epilepsy
Neurochemical research, 1991
Epileptogenic conditions come about from a disequilibrium between excitatory and inhibitory mechanisms, creating a state of neuronal hypersynchrony. From experimental studies in animal models of epilepsy it appears that several mechanisms, alone or in combination, could be responsible for this imbalance. An alteration of GABA-mediated inhibition has long been considered to be one of the most likely candidates. We review recent data on the synaptie physiology of GABAmediated inhibition, with emphasis on GABAA and GABAB receptors and their conductances. We describe the integrative role of GABAergic local-circuit neurons in the normal control of recurrent excitation. We then discuss possible alterations in GABAA-mediated inhibition in two chronic animal models of epilepsy, the kindled rat and the kainate-treated rat. Finally, we review studies on GABA inhibition in human epileptic cortex resected for the treatment of intractable epilepsy.
GABA Potency at GABAA Receptors Found in Synaptic and Extrasynaptic Zones
Frontiers in Cellular Neuroscience, 2012
The potency of GABA is vitally important for its primary role in activating GABA A receptors and acting as an inhibitory neurotransmitter. Although numerous laboratories have presented information, directly or indirectly, on GABA potency, it is often difficult to compare across such studies given the inevitable variations in the methods used, the cell types studied, whether native or recombinant receptors are examined, and their relevance to native synaptic and extrasynaptic GABA A receptors. In this review, we list the most relevant isoforms of synaptic and extrasynaptic GABA A receptors that are thought to assemble in surface membranes of neurons in the central nervous system. Using consistent methodology in one cell type, the potencies of the endogenous neurotransmitter GABA are compared across a spectrum of GABA A receptors. The highest potency for GABA is measured when activating extrasynaptic-type α6 subunit-containing receptors, whereas synaptic-type α2β3γ2 and α3β3γ2 receptors exhibited the lowest potency, and other GABA A receptor subtypes that are found both in synaptic and extrasynaptic compartments, showed intermediate sensitivities to GABA. The relatively simple potency relationship between GABA and its target receptors is important as it serves as one of the major determinants of GABA A receptor activation, with consequences for the development of inhibition, either by tonic or phasic mechanisms.
Multiple and Plastic Receptors Mediate Tonic GABAA Receptor Currents in the Hippocampus
Journal of Neuroscience, 2005
Persistent activation of GABA A receptors by extracellular GABA (tonic inhibition) plays a critical role in signal processing and network excitability in the brain. In hippocampal principal cells, tonic inhibition has been reported to be mediated by ␣5-subunit-containing GABA A receptors (␣5GABA A Rs). Pharmacological or genetic disruption of these receptors improves cognitive performance, suggesting that tonic inhibition has an adverse effect on information processing. Here, we show that ␣5GABA A Rs contribute to tonic currents in pyramidal cells only when ambient GABA concentrations increase (as may occur during increased brain activity). At low ambient GABA concentrations, activation of ␦-subunit-containing GABA A receptors predominates. In epileptic tissue, ␣5GABA A Rs are downregulated and no longer contribute to tonic currents under conditions of raised extracellular GABA concentrations. Under these conditions, however, the tonic current is greater in pyramidal cells from epileptic tissue than in pyramidal cells from nonepileptic tissue, implying substitution of ␣5GABA A Rs by other GABA A receptor subtypes. These results reveal multiple components of tonic GABA A receptormediated conductance that are activated by low GABA concentrations. The relative contribution of these components changes after the induction of epilepsy, implying an adaptive plasticity of the tonic current in the presence of spontaneous seizures.
Regulation of excitability by extrasynaptic GABAA receptors
Results and Problems in Cell Differentiation, 2007
Not only are GABA A receptors activated transiently by GABA released at synapses, but high affinity, extrasynaptic GABA A receptors are also activated by ambient, extracellular GABA as a more persistent form of signalling (often termed tonic inhibition). Over the last decade tonic GABA A receptor-mediated inhibition and the properties of GABA A receptors mediating this signalling have received increasing attention. Tonic inhibition is present throughout the central nervous system, but is expressed in a cell-type specific manner (e.g. in interneurons more so than in pyramidal cells in the hippocampus, and in thalamocortical neurons more so than in reticular thalamic neurons in the thalamus). As a consequence, tonic inhibition can have a complex effect on network activity. Tonic inhibition is not fixed but can be modulated by endogenous and exogenous modulators, such as neurosteroids, and by developmental, physiological and pathological regulation of GABA uptake and GABA A receptor expression. There is also growing evidence that tonic currents play an important role in epilepsy, sleep (also actions of anaesthetics and sedatives), memory and cognition. Therefore, drugs specifically aimed at targeting the extrasynaptic receptors involved in tonic inhibition could be a novel approach to regulating both physiological and pathological processes.