Perisynaptic GABA Receptors: The Overzealous Protector

Clarkson, Andrew N.

doi:https://doi.org/10.1155/2012/708428

Advances in Pharmacological and Pharmaceutical Sciences

On this page

Abstract Conclusions Acknowledgments References Copyright Related Articles

Special Issue

GABA<sub>A</sub> Receptor Subtypes: Novel Targets for Novel Medicines

View this Special Issue

Review Article | Open Access

Volume 2012 | Article ID 708428 | https://doi.org/10.1155/2012/708428

Perisynaptic GABA Receptors: The Overzealous Protector

Andrew N. Clarkson¹

Academic Editor: John Atack

Received13 Apr 2011

Accepted12 Dec 2011

Published22 Feb 2012

Abstract

An attempt to find pharmacological therapies to treat stroke patients and minimize the extent of cell death has seen the failure of dozens of clinical trials. As a result, stroke/cerebral ischemia is the leading cause of lasting adult disability. Stroke-induced cell death occurs due to an excess release of glutamate. As a consequence to this, a compensatory increased release of GABA occurs that results in the subsequent internalization of synaptic GABA_A receptors and spillover onto perisynaptic GABA_A receptors, resulting in increased tonic inhibition. Recent studies show that the brain can engage in a limited process of neural repair after stroke. Changes in cortical sensory and motor maps and alterations in axonal structure are dependent on patterned neuronal activity. It has been assumed that changes in neuronal excitability underlie processes of neural repair and remapping of cortical sensory and motor representations. Indeed, recent evidence suggests that local inhibitory and excitatory currents are altered after stroke and modulation of these networks to enhance excitability during the repair phase can facilitate functional recovery after stroke. More specifically, dampening tonic GABA inhibition can afford an early and robust improvement in functional recovery after stroke.

1. -Aminobutyric Acid (GABA)

GABA is the major inhibitory neurotransmitter within the mammalian brain. Twenty to 50% of all synapses within the CNS use GABA as a neurotransmitter, mediating both fast and slow inhibitory synaptic transmission [1]. GABA is an endogenous ligand for the GABA_A, GABA_B, and GABA_C receptors [2], and these receptor subtypes have been classified according to differences in both structure and pharmacology. GABA_ARs are ligand-gated chloride channels [2, 3] formed from 5 subunits arranged around a central ion pore. At least nineteen mammalian genes encoding for the various GABA_AR subunits exist: , , , δ, ε, φ, π, and , with slice variants also contributing to variations in receptor functions [4–9]. The most common subunit combinations are believed to be composed of 2α, 2β, and γ, with the γ-subunit being able to be substituted for either an ε- or a δ-subunit [7–9].

Depolarization of inhibitory interneurons produces a phasic release of GABA and inhibition of postsynaptic neurons. Extrasynaptic GABA_AR’s respond to ambient levels of GABA present in the extracellular space to regulate baseline pyramidal neuron excitability and show reduced desensitization remaining active for long periods of time [10]. Tonic GABA_AR’s in the hippocampus and cortex contain either α5 or δ-subunits [6, 10]. Reduced activity of α5 or δ-subunits enhances pyramidal neuron firing to afferent inputs [10–12], enhances neuronal network excitability [13], and facilitates LTP and cognitive performance [14–17]. GABA transporters modulate the level of tonic GABA_AR activity [18] with the uptake of GABA into neurons and astrocytes for recycling. Low GABA concentrations activate extrasynaptic GABA_AR’s, leading to persistent or tonic inhibition [19, 20]. Synaptic and extrasynaptic GABA_AR’s exhibit distinct pharmacological and biophysical properties that differentially influence brain physiology and behavior [19].

Synaptic GABA_AR’s are composed of , , and , subunits, and the site of action for a variety of clinically important drugs, such as benzodiazepines, neurosteroids, and anesthetics. Where as extrasynaptic GABA_AR’s are composed of subunit combinations containing , , and - or δ-subunits. Of these receptors, the δ-containing GABA_AR’s coassembled as α₄βδ—located in the cortex, hippocampus and thalamus—or α₆βδ—located in the cerebellum—that are emerging as unique and fundamental players in GABAergic neurotransmission [19]. In addition to δ-containing GABA_AR’s having a functional role in the cortex, the α5-containing GABA_AR’s coassembled primarily as α₅βγ₂ have also been implicated in poststroke repair [21]. Even though the expression of the α5-subunit is low in the cortex compared to the δ-subunit, greater functional improvements in motor recovery are seen following modulation of the α5-subunit [21]. The pharmacology of these extrasynaptic receptors is inconsistent between research groups [22] and has been hampered by the lack of selective agents to probe function in recombinant, native, and whole animal systems [23]. Conflicting data is also present with respect for the ability of these receptors to desensitize [19, 24]. Determining the composition and pharmacology of this receptor will enable the development of much needed therapies for use in stroke.

1.1. Disability in Stroke

Stroke is the leading cause of death and long-term disability in adults worldwide. Stroke-induced sensory and motor loss of limb function, in particular, prevents patients from returning to work and accounts for the statistic that almost one-third of stroke survivors become institutionalized after having a stroke [25–28]. Recent studies have shown that the brain has a limited capacity to repair after stroke. In both humans and animals, neural repair after stroke has been shown to involve remapping of cognitive functions and sprouting of new connections in tissue adjacent to the stroke site, the peri-infarct cortex [29, 30]. However, mechanisms associated with poststroke neural repair and recovery have not been well characterized, and it has been assumed that changes in cortical representational maps underlying the recovery involve changes in neuronal excitability. Consistent with this, animal studies suggest that therapies associated with rehabilitation can promote plasticity changes in tissue that survives the stroke [31].

Functional recovery within the peri-infarct cortex involves changes in neuronal excitability. Clinical studies using direct current stimulation of the peri-infarct cortex, with protocols that boost local neuronal excitability, have been shown to improve use of the affected limb in stroke patients [32, 33]. Furthermore, forced use or task-specific repetition of the affected limb have also been shown to activate the peri-infarct cortex and improve functional recovery [34]. Studies suggest that decreases in γ-aminobutyric acid GABA activity within the motor cortex could facilitate structural changes [35] and promote recovery of motor function [36]. Alterations in neuronal excitability underlie fundamental changes in information transfer in neuronal circuits [37] such as long-term potentiation and depression (LTP and LTD) as well as the unmasking of quiescent synaptic connections and remodeling of cortical maps [38]. Furthermore, changes in LTP and cortical map formation occur within the peri-infarct cortex adjacent to the stroke [29]. These data suggest a critical role for modulating cortical excitability as a means for promoting functional recovery after stroke.

1.2. Brain Excitability in Learning, Memory, and Repair

The processes of neurorehabilitation involve physical, occupational, and cognitive therapies [27, 28]. Further changes in poststroke cortical plasticity play a critical role in mediating repair mechanisms. While these modalities clearly promote functional recovery, no drug treatments exist that promote poststroke brain repair and recovery. Recent evidence suggests that suppression of either cortical tonic GABA inhibition or stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents can promote poststroke function gain [21, 39]. This ability to regain function relies heavily on the ability to learn or relearn after stroke and likely follows classical activity-dependent processes associated with motor learning and memory [40, 41]. In addition to these behavioral links, stroke recovery and classical learning and memory pathways share similar molecular and cellular links. For instance, genes that are important for learning and memory are also elevated during periods of poststroke repair and include membrane-associated phosphoproteins GAP43 and MARCKS, the transcription factor c-jun, and the cell adhesion molecule L1 [42].

Modulation of learning and memory pathways have previously been shown to promote functional recovery and poststroke axonal sprouting following administration of pharmacological agents such as amphetamines and phosphodiesterase type-4 inhibitors that boost cAMP/CREB signaling and learning and memory function [43, 44]. These data indicate that manipulating learning and memory pathways can offer a novel means for promoting recovery. As with stroke recovery, the processes of learning and memory can be enhanced by manipulations that increase neuronal excitability, which has also been shown to promote function recovery [21]. Significant data is accumulating indicating an imbalance in inhibitory and excitatory pathways after stroke, and modulation of these pathways by either enhancing glutamate-mediated transmission or dampening the tonic form of GABA can facilitate functional recovery [21, 39, 45–48]. α5GABA_AR negative allosteric modulators are part of a broad class of drugs that boost learning and memory function by influencing key elements in neuronal memory storage, such as LTP [14, 16]. α5GABA_AR negative allosteric modulators, and indeed any mechanism that dampens tonic GABA signaling, could significantly improve poststroke recovery [21]. This suggests that the similarities between neuronal mechanisms of learning and memory and those of functional recovery after stroke extend to common treatment strategies for both.

Most strategies that promote functional recovery after stroke, such as axonal sprouting, neurogenesis, or angiogenesis, focus or rely on inducing structural changes in the brain as a means to promote functional recovery after stroke [49–53]. In order to promote structural change in the brain, however, these treatments take time to develop a functional effect. Blocking tonic GABA inhibition induces a rapid improvement in behavioral recovery in the absence of any change in axonal sprouting within the peri-infarct cortex [21]. This data suggests that treatments that focus on inducing molecular memory systems after stroke may have the advantage of promoting synaptic plasticity in peri-infarct cortex rapidly and without altering the tissue reorganization that normally occurs after stroke. These therapies are highly translatable into the clinic due to their timing of drug administration, 3–7 days after stroke in rodents, and with the early effects seen with functional recovery, will aid in the huge social and economical burdens seen after stroke.

1.3. Attenuating GABAA Receptor Function in Neural Repair after Stroke

As with stroke recovery, the processes of learning and memory can be enhanced by manipulations that increase neuronal excitability. However, unlike the stroke recovery field, basic science studies in learning and memory have defined specific cellular pathways that lead to enhanced neuronal excitability and improved function.

Recent work has shown that enhanced neuronal excitability occurs following the dampening of the baseline level of inhibition in neurons. This baseline inhibition is in part set by a tonic, always present, degree of inhibitory signaling from the major inhibitory neurotransmitter, GABA. Unlike the phasic nature of synaptically released GABA, the action of GABA via extrasynaptic receptors is to tonically suppress neuronal excitability and to help regulate neuronal action potential firing. These extrasynaptic GABA receptors consist of α5 and δ-subunit containing GABA_AR’s. Recent evidence using α5GABA_AR “knock-out”, and point-mutated mice have clearly shown that the α5-subunit plays a key role in cognitive processing [15, 17]. In addition, in vitro and in vivo work has shown that α5GABA_AR negative allosteric modulators can enhance cognition within the Morris water maze, enhance hippocampal LTP and do not have any proconvulsant effects [14, 16]. Using pharmacological and genetic manipulations of extrasynaptic GABA_AR’s, we have shown marked improvements in functional recovery when starting treatments from 3 days after the stroke [21]. These data are consistent for offering a potential role for extrasynaptic GABA_AR’s in processes involving synaptic plasticity and learning and memory and more recently poststroke recovery.

Neuronal inhibition and network function is disturbed in peri-infarct tissue during periods of cortical plasticity, re-mapping, and recovery. The increase in tonic inhibition in cortical pyramidal neurons reported by Clarkson and colleagues [21] occurs at precisely the same time as cortical map plasticity and recovery [54]. Behavioral recovery in stroke is closely correlated with functional plasticity in peri-infarct and connected cortical regions. In human stroke patients, an expansion in motor representation maps is seen in tissue adjacent to or connected to stroke [29, 55]. In animal models, when stroke damages primary motor or somatosensory areas, motor and sensory representations remap in peri-infarct cortex [54, 56]. These processes of recovery identify plasticity in the cortical circuits in peri-infarct cortex as key elements in functional recovery.

2. GABA and Cerebral Ischemia

A large body of work has been devoted to developing and exploring neuroprotectants that act to block glutamate-mediated neurotransmission in animal models of cerebral ischemia [57, 58]. Increased inhibitory neurotransmission associated with GABA has been shown to normalize the balance of glutamate-mediated excitation. Therefore, pharmacological enhancement of GABA_AR neurotransmission provides an alternative means for neuroprotection. Indeed, over recent years, changes in GABA function following cerebral ischemia and possible protective benefits of GABAergic drugs have been extensively assessed [59–65]. Even though it has been proposed that enhancing GABA transmission may elicit protection against cerebral ischemia [60–62, 65], the exact mechanisms that are associated with these neuroprotectants have, as yet, not been fully elucidated and increasing GABA function may be protective during cerebral ischemia for different reasons [59–65]. However, even though GABA agonists have shown great promise in animal model, these compounds have failed to translate into the clinic [66, 67]. The failure of these compounds highlights the need to firstly establish better preclinical rodent models of stroke that better mimic what occurs in humans. Secondly, the use of subunit specific GABA compounds is more likely to show an effect, due to them having less side effects, such as drug-induced hypothermia and sedation. However, even with recent developments in this area, studies are lacking. The need to assess subunit-specific GABA compounds to help understand what is happening after stroke in terms of GABA function is highlighted with clinical reports showing that zolpidem, an α1 subunit GABA_AR modulator, can result in transiently improves in aphasia in chronic stroke survivors [68].

During situations of cerebral ischemia, it has been shown that the extracellular concentrations of GABA increase (approx. 50 fold compared to basal levels) to the micromolar range [59, 69] and remain elevated for at least 30 minutes during periods of reperfusion. Prolonged exposure of the GABA_ARs to high concentrations of GABA agonists in vitro has routinely been shown to become desensitized and/or downregulated [70–72]. Similarly, the GABA_AR is also downregulated in the gerbil hippocampus following transient cerebral ischemia [63]. In this model, receptor downregulation was shown to be via internalization, as there was a rapid decrease in binding of the hydrophilic ligand [3H]-SR-95531, but not the hydrophobic ligand [3H]-flunitrazepam [63]. This increase in extracellular GABA is likely to result in the spill over onto peri-synaptic GABA_AR’s resulting in an increase in tonic inhibition. Indeed, recent evidence showing an increase in tonic inhibition after stroke supports this notion [21]. This increase in tonic inhibition is most likely a safety mechanism imposed by the brain as a means to minimize neuronal damage. However, as this increase in tonic inhibition persists for at least 2 weeks after the stroke, this safety mechanism which is likely to have either wrong or no feedback mechanism has been formed to compensate for such a change in tonic GABA.

3. Poststroke Tonic Inhibition

Changes in neuronal excitability, loss of GABAergic inhibition, enhanced glutamatergic transmission, and synaptic plasticity all contribute to neuronal reorganization after stroke. Studies that promote an increase in local brain excitability result in improved function [21, 34, 39, 45] and suggest that decreasing GABA activity within the brain could facilitate structural changes that promote functional recovery [21, 34, 45]. In particular, this enhancement of neuronal excitability involves dampening baseline levels of inhibition.

Tonic or continuous signaling from GABA sets baseline inhibition. GABA acts via extrasynaptic GABA_AR’s to tonically suppress neuronal excitability and regulate neuronal action potential firing. Therefore, in order to facilitate functional recovery, an increase in brain excitability is required to overcome this hypofunctionalism [34]. Recently Clarkson and colleagues have demonstrated marked improvements in poststroke functional recovery using pharmacological manipulations of extrasynaptic GABA_AR’s, implicating α5 or δ-containing GABA_AR’s as novel targets for developing agents to help stroke sufferers.

GABA has been shown to mediate both fast and slow inhibitory synaptic transmission [1]. During development, however, the GABA_ARs have been shown to mediate excitation as well as play an important role in neural migration and synaptogenesis [73, 74]. During situations of cerebral ischemia, extracellular concentrations of GABA are significantly elevated [59, 69], resulting in GABA_A receptor desensitization and/or downregulation [63, 71]. This is supported by immunohistochemical and autoradiographic data showing decreased expression of α1, α2, α3, α5, and γ2 subunits following photothrombotic stroke and freeze-lesion-induced cortical injury [75–77].

Recent work has shown that epileptogenesis results in the suppression of functionally active α5GABA_ARs and results in an increase/substitution of other GABA_AR’s with a subsequent increase in rather than suppression of tonic inhibitory currents [78]. A similar compensatory increase in α4δ-mediated tonic currents has been seen in the α5 knockout mice within region CA1 of the hippocampus [11]. Extracellular GABA concentrations and thus tonic inhibition have been shown to increase as the excitatory drive increases resulting in the modulation of neuronal excitability and prevention of neuronal saturation [79]. Consistent with these findings, Clarkson and colleagues reported an increase in GABA tonic inhibitory currents from 3–14 days poststroke in layer II cortical pyramidal neurons [21]. This poststroke increase in tonic inhibition may act as a compensatory mechanism to prevent further neuronal injury. However, this prolonged increase in tonic inhibition during the repair phase is acting as a hindrance by preventing cortical expansion and improvements in functional recovery. This is supported by findings by Clarkson and colleagues who show that both pharmacological and genetic modulation of tonic inhibition, dampening either α5 or δ-mediated increase in tonic GABA currents, results in early and marked improvements in functional recovery [21].

Understanding the profile for which cortical plasticity occurs, altered after a stroke, is critical for fully determining when to start treatments and with what therapeutic compound to use. Based on our findings, we have clearly shown that dampening of tonic GABA currently from 3 days results in robust functional improvements of motor recovery [21]. These improvements, however, may not be the same if treatments are started weeks after stroke onset as previously shown in humans using zolpidem, which was shown to transiently improve aphasia in chronic stroke survivors [68]. The α1 and β2 GABA_AR subunits are densely localized within the cortex and coassembly with the γ2-subunit accounts for about 40% of all GABA_ARs within the cortex [80]. Assembly of GABA_ARs containing α1β2γ2 has been shown to be enriched at synaptic sites throughout the cortex [81] and involved in changes in synaptic plasticity. However, studies have also shown that the δ subunit can coassemble with α1 subunits to form functional recombinant receptors[82, 83]. Furthermore, immunoprecipitation studies have shown that δ subunits can associate with α1 subunits [84], and GABA_ARα1 subunits have also been found extrasynaptically [85, 86] consistent with the typical localization of δ-containing GABA_ARs⁸¹⁸¹. These data could suggest an alternative method for why zolpidem was having an effect in chronic stroke patients to alleviate the burden of aphasia. However, further studies are needed, as one previous study would suggest that the γ2-subunit is required in order for zolpidem to have an effect [87].

4. Dampening Cortical Inhibition Alters Cortical Responsiveness

Disinhibition of cortical connections within the peri-infarct or regions associated with the peri-infarct cortex have been argued as either occurring as a direct consequence of the stroke or as a potential compensatory mechanism related to the recovery [88]. This argument has come about based on a number of observations such as local blockage of GABAergic inhibition unmasking preexisting horizontal connections within the rat motor cortex [38]; LTP of adult rat motor cortex horizontal connections is dependent on GABA disinhibition during theta burst stimulation, unlike other regions such as the hippocampus or somatosensory cortex [35]; and finally modulation of GABA has been shown to be involved in learning in healthy humans as shown using imaging studies showing a correlation between a decrease in GABA concentration in motor cortex and motor skill learning [89]. Consistent with the notion that cortical disinhibition is occurring as a compensatory mechanism, Clarkson and colleagues have shown a robust and persistent increase in tonic inhibition in the peri-infarct cortex after stroke and blockade of this tonic inhibition at the time of stroke with the extrasynaptic GABA_AR negative allosteric modulator, L655-708, exacerbated the lesion [21]. Further to this, Clarkson and colleagues showed for the first time that delayed treatment L655-708, which has previously been shown to induce LTP [14], provides an early and robust reversal in behavioral deficits [21]. Given the early behavioral effects seen and the lack of effect on sprouting of new connections, cortical disinhibition following L655-708-treatment seems a logical argument. To support the notion that dampening GABA activity is having a beneficial effect, no improvement in motor function was observed after stroke following administration of the GABA agonist, muscimol [21]. This is backed by clinical studies illustrating the reemergence of stroke symptoms following administration of the GABA agonist midazolam in chronic stroke patients that have shown significant improvements in function [90]. The peri-infarct cortex exhibits neuronal metabolic dysfunction over a one-month period [91], which would indicate a therapeutic time window for blockade of tonic GABA signaling of at least one month after stroke. Consistent with this is the fact, when L655-708 treatment is discontinued after a two-week period of administration after stroke, a slight rebound effect/reversal in functional recovery is observed compared to animals that received treatment for the six-week period [21].

5. Conclusions

Therapies that promote functional recovery after stroke are limited to physical rehabilitation measures. While specific measures, such as constraint-induced therapies, promote recovery of motor function, no pharmacological therapies are available that aid in recovery. Functional recovery after stroke follows psychological learning rules [41] that indicate learning and memory principles may underlie behavioral recovery. At the cellular level, learning and memory are mediated by specific excitatory neuronal responses, such as LTP, and are potentiated by drugs that facilitate aspects of excitatory neuronal signaling [13], such as tonic GABA_AR antagonists [10]. Recent data shows that stroke alters the balance of excitatory and inhibitory inputs to neurons in the peri-infarct cortex, by increasing inhibitory tone. This altered excitatory balance occurs through a decrease in the normal cellular uptake of GABA. Dampening GABA-mediated tonic inhibition restores the excitatory/inhibitory balance in peri-infarct motor cortex ex vivo and promotes recovery of motor function in vivo. These effects occur through blockade of α5 or δ-containing GABA_AR’s. This data indicates a novel role for tonic GABA_AR function in promoting poststroke recovery most likely via cortical disinhibition [38, 92, 93] and suggests a new avenue for pharmacological treatment of neurorehabilitation in stroke. This early effect on stroke recovery opens the possibility for treatments that block tonic GABA signaling and may be used in conjunction with later-acting stroke repair therapies in a combinatorial manner. More generally, tonic GABA signaling has a biphasic role in stroke. Early tonic GABA signaling limits stroke size, later tonic GABA signaling limits stroke recovery. These data identify a promising molecular system for future stroke recovery therapies and implicate molecular memory systems as likely key players in recovery from stroke.

Acknowledgments

This paper was completed during tenure of a Repatriation Fellowship from the New Zealand Neurological Foundation and the Sir Charles Hercus Fellowship from the Health Research Council of New Zealand.

References

W. Sieghart, “Structure and pharmacology of γ-aminobutyric acid(A) receptor subtypes,” Pharmacological Reviews, vol. 47, no. 2, pp. 181–234, 1995.
View at: Google Scholar
M. Chebib and G. A. R. Johnston, “The “ABC” of GABA receptors: a brief review,” Clinical and Experimental Pharmacology and Physiology, vol. 26, no. 11, pp. 937–940, 1999.
View at: Publisher Site | Google Scholar
C. D'Hulst, J. R. Atack, and R. F. Kooy, “The complexity of the GABA_A receptor shapes unique pharmacological profiles,” Drug Discovery Today, vol. 14, no. 17-18, pp. 866–875, 2009.
View at: Publisher Site | Google Scholar
R. L. Macdonald and R. W. Olsen, “GABAA receptor channels,” Annual Review of Neuroscience, vol. 17, pp. 569–602, 1994.
View at: Google Scholar
R. W. Olsen and W. Sieghart, “International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit composition, pharmacology, and function. Update,” Pharmacological Reviews, vol. 60, no. 3, pp. 243–260, 2008.
View at: Publisher Site | Google Scholar
R. W. Olsen and W. Sieghart, “GABA_A receptors: subtypes provide diversity of function and pharmacology,” Neuropharmacology, vol. 56, no. 1, pp. 141–148, 2009.
View at: Publisher Site | Google Scholar
N. P. Barrera, J. Betts, H. You et al., “Atomic force microscopy reveals the stoichiometry and subunit arrangement of the α₄β₃δ GABA_A receptor,” Molecular Pharmacology, vol. 73, no. 3, pp. 960–967, 2008.
View at: Publisher Site | Google Scholar
P. J. Whiting, “The GABAA receptor gene family: new opportunities for drug development,” Current Opinion in Drug Discovery and Development, vol. 6, no. 5, pp. 648–657, 2003.
View at: Google Scholar
P. J. Whiting, “GABA-A receptor subtypes in the brain: a paradigm for CNS drug discovery?” Drug Discovery Today, vol. 8, no. 10, pp. 445–450, 2003.
View at: Publisher Site | Google Scholar
J. Glykys and I. Mody, “Activation of GABA_A receptors: views from outside the synaptic cleft,” Neuron, vol. 56, no. 5, pp. 763–770, 2007.
View at: Publisher Site | Google Scholar
J. Glykys and I. Mody, “Hippocampal network hyperactivity after selective reduction of tonic inhibition in GABA_A receptor α5 subunit-deficient mice,” Journal of Neurophysiology, vol. 95, no. 5, pp. 2796–2807, 2006.
View at: Publisher Site | Google Scholar
K. R. Drasbek and K. Jensen, “THIP, a hypnotic and antinociceptive drug, enhances an extrasynaptic GABA_A receptor-mediated conductance in mouse neocortex,” Cerebral Cortex, vol. 16, no. 8, pp. 1134–1141, 2006.
View at: Publisher Site | Google Scholar
M. C. Walker and A. Semyanov, “Regulation of excitability by extrasynaptic GABAA receptors,” Results and Problems in Cell Differentiation, vol. 44, pp. 29–48, 2008.
View at: Publisher Site | Google Scholar
J. R. Atack, P. J. Bayley, G. R. Seabrook, K. A. Wafford, R. M. McKernan, and G. R. Dawson, “L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for α5-containing GABAA receptors,” Neuropharmacology, vol. 51, no. 6, pp. 1023–1029, 2006.
View at: Publisher Site | Google Scholar
N. Collinson, F. M. Kuenzi, W. Jarolimek et al., “Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the α5 subunit of the GABAA receptor,” Journal of Neuroscience, vol. 22, no. 13, pp. 5572–5580, 2002.
View at: Google Scholar
G. R. Dawson, K. A. Maubach, N. Collinson et al., “An inverse agonist selective for α5 subunit-containing GABA A receptors enhances cognition,” Journal of Pharmacology and Experimental Therapeutics, vol. 316, no. 3, pp. 1335–1345, 2006.
View at: Publisher Site | Google Scholar
F. Crestani, R. Keist, J. M. Fritschy et al., “Trace fear conditioning involves hippocampal α5 GABAA receptors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 13, pp. 8980–8985, 2002.
View at: Publisher Site | Google Scholar
S. Keros and J. J. Hablitz, “Subtype-specific GABA transporter antagonists synergistically modulate phasic and tonic GABAA conductances in rat neocortex,” Journal of Neurophysiology, vol. 94, no. 3, pp. 2073–2085, 2005.
View at: Publisher Site | Google Scholar
D. Belelli, N. L. Harrison, J. Maguire, R. L. Macdonald, M. C. Walker, and D. W. Cope, “Extrasynaptic GABAa receptors: form, pharmacology, and function,” Journal of Neuroscience, vol. 29, no. 41, pp. 12757–12763, 2009.
View at: Publisher Site | Google Scholar
I. Mody, “Distinguishing between GABAA receptors responsible for tonic and phasic conductances,” Neurochemical Research, vol. 26, no. 8-9, pp. 907–913, 2001.
View at: Publisher Site | Google Scholar
A. N. Clarkson, B. S. Huang, S. E. MacIsaac, I. Mody, and S. T. Carmichael, “Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke,” Nature, vol. 468, no. 7321, pp. 305–309, 2010.
View at: Publisher Site | Google Scholar
C. M. Borghese and R. A. Harris, “Studies of ethanol actions on recombinant δ-containing γ-aminobutyric acid type A receptors yield contradictory results,” Alcohol, vol. 41, no. 3, pp. 155–162, 2007.
View at: Publisher Site | Google Scholar
K. A. Wafford, M. B. van Niel, Q. P. Ma et al., “Novel compounds selectively enhance δ subunit containing GABAA receptors and increase tonic currents in thalamus,” Neuropharmacology, vol. 56, no. 1, pp. 182–189, 2009.
View at: Publisher Site | Google Scholar
D. P. Bright, M. Renzi, J. Bartram et al., “Profound desensitization by ambient GABA limits activation of δ-containing GABA_A receptors during spillover,” Journal of Neuroscience, vol. 31, no. 2, pp. 753–763, 2011.
View at: Publisher Site | Google Scholar
Y. S. Ng, J. Stein, M. Ning, and R. M. Black-Schaffer, “Comparison of clinical characteristics and functional outcomes of ischemic stroke in different vascular territories,” Stroke, vol. 38, no. 8, pp. 2309–2314, 2007.
View at: Publisher Site | Google Scholar
S. M. Lai, S. Studenski, P. W. Duncan, and S. Perera, “Persisting consequences of stroke measured by the stroke impact scale,” Stroke, vol. 33, no. 7, pp. 1840–1844, 2002.
View at: Publisher Site | Google Scholar
B. H. Dobkin, “Training and exercise to drive poststroke recovery,” Nature Clinical Practice Neurology, vol. 4, no. 2, pp. 76–85, 2008.
View at: Publisher Site | Google Scholar
B. H. Dobkin, “Strategies for stroke rehabilitation,” Lancet Neurology, vol. 3, no. 9, pp. 528–536, 2004.
View at: Publisher Site | Google Scholar
S. T. Carmichael, “Cellular and molecular mechanisms of neural repair after stroke: making waves,” Annals of Neurology, vol. 59, no. 5, pp. 735–742, 2006.
View at: Publisher Site | Google Scholar
R. J. Nudo, “Mechanisms for recovery of motor function following cortical damage,” Current Opinion in Neurobiology, vol. 16, no. 6, pp. 638–644, 2006.
View at: Publisher Site | Google Scholar
M. A. Maldonado, R. P. Allred, E. L. Felthauser, and T. A. Jones, “Motor skill training, but not voluntary exercise, improves skilled reaching after unilateral ischemic lesions of the sensorimotor cortex in rats,” Neurorehabilitation and Neural Repair, vol. 22, no. 3, pp. 250–261, 2008.
View at: Publisher Site | Google Scholar
M. Alonso-Alonso, F. Fregni, and A. Pascual-Leone, “Brain stimulation in poststroke rehabilitation,” Cerebrovascular Diseases, vol. 24, no. 1, supplement 1, pp. 157–166, 2007.
View at: Publisher Site | Google Scholar
F. C. Hummel and L. G. Cohen, “Non-invasive brain stimulation: a new strategy to improve neurorehabilitation after stroke?” Lancet Neurology, vol. 5, no. 8, pp. 708–712, 2006.
View at: Publisher Site | Google Scholar
G. F. Wittenberg and J. D. Schaechter, “The neural basis of constraint-induced movement therapy,” Current Opinion in Neurology, vol. 22, no. 6, pp. 582–588, 2009.
View at: Publisher Site | Google Scholar
G. Hess, C. D. Aizenman, and J. P. Donoghue, “Conditions for the induction of long-term potentiation in layer II/III horizontal connections of the rat motor cortex,” Journal of Neurophysiology, vol. 75, no. 5, pp. 1765–1778, 1996.
View at: Google Scholar
P. Cicinelli, P. Pasqualetti, M. Zaccagnini, R. Traversa, M. Olivefi, and P. M. Rossini, “Interhemispheric asymmetries of motor cortex excitability in the postacute stroke stage: a paired-pulse transcranial magnetic stimulation study,” Stroke, vol. 34, no. 11, pp. 2653–2658, 2003.
View at: Publisher Site | Google Scholar
A. Citri and R. C. Malenka, “Synaptic plasticity: multiple forms, functions, and mechanisms,” Neuropsychopharmacology, vol. 33, no. 1, pp. 18–41, 2008.
View at: Publisher Site | Google Scholar
K. M. Jacobs and J. P. Donoghue, “Reshaping the cortical motor map by unmasking latent intracortical connections,” Science, vol. 251, no. 4996, pp. 944–947, 1991.
View at: Google Scholar
A. N. Clarkson, J. J. Overman, S. Zhong, R. Mueller, G. Lynch, and S. T. Carmichael, “AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke,” Journal of Neuroscience, vol. 31, no. 10, pp. 3766–3775, 2011.
View at: Publisher Site | Google Scholar
J. M. Conner, A. A. Chiba, and M. H. Tuszynski, “The basal forebrain cholinergic system is essential for cortical plasticity and functional recovery following brain injury,” Neuron, vol. 46, no. 2, pp. 173–179, 2005.
View at: Publisher Site | Google Scholar
J. W. Krakauer, “Motor learning: its relevance to stroke recovery and neurorehabilitation,” Current Opinion in Neurology, vol. 19, no. 1, pp. 84–90, 2006.
View at: Google Scholar
S. T. Carmichael, I. Archibeque, L. Luke, T. Nolan, J. Momiy, and S. Li, “Growth-associated gene expression after stroke: evidence for a growth-promoting region in peri-infarct cortex,” Experimental Neurology, vol. 193, no. 2, pp. 291–311, 2005.
View at: Publisher Site | Google Scholar
R. P. Stroemer, T. A. Kent, and C. E. Hulsebosch, “Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats,” Stroke, vol. 29, no. 11, pp. 2381–2395, 1998.
View at: Google Scholar
E. MacDonald, H. van der Lee, D. Pocock et al., “A novel phosphodiesterase type 4 inhibitor, HT-0712, enhances rehabilitation-dependent motor recovery and cortical reorganization after focal cortical ischemia,” Neurorehabilitation and Neural Repair, vol. 21, no. 6, pp. 486–496, 2007.
View at: Publisher Site | Google Scholar
A. N. Clarkson and S. T. Carmichael, “Cortical excitability and post-stroke recovery,” Biochemical Society Transactions, vol. 37, no. 6, pp. 1412–1414, 2009.
View at: Publisher Site | Google Scholar
S. Schmidt, C. Bruehl, C. Frahm, C. Redecker, and O. W. Witte, “Age dependence of excitatory-inhibitorybalance following stroke,” Neurobiology of Aging. In press.
View at: Publisher Site | Google Scholar
S. Schmidt, C. Redecker, C. Bruehl, and O. W. Witte, “Age-related decline of functional inhibition in rat cortex,” Neurobiology of Aging, vol. 31, no. 3, pp. 504–511, 2010.
View at: Publisher Site | Google Scholar
N. Jaenisch, O. W. Witte, and C. Frahm, “Downregulation of potassium chloride cotransporter KCC2 after transient focal cerebral ischemia,” Stroke, vol. 41, no. 3, pp. e151–e159, 2010.
View at: Publisher Site | Google Scholar
S. T. Carmichael, “Targets for neural repair therapies after stroke,” Stroke, vol. 41, no. 10, supplement, pp. S124–S126, 2010.
View at: Publisher Site | Google Scholar
S. T. Carmichael, “Themes and strategies for studying the biology of stroke recovery in the poststroke epoch,” Stroke, vol. 39, no. 4, pp. 1380–1388, 2008.
View at: Publisher Site | Google Scholar
J. J. Ohab, S. Fleming, A. Blesch, and S. T. Carmichael, “A neurovascular niche for neurogenesis after stroke,” Journal of Neuroscience, vol. 26, no. 50, pp. 13007–13016, 2006.
View at: Publisher Site | Google Scholar
Z. G. Zhang and M. Chopp, “Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic,” The Lancet Neurology, vol. 8, no. 5, pp. 491–500, 2009.
View at: Publisher Site | Google Scholar
J. Liauw, S. Hoang, M. Choi et al., “Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 10, pp. 1722–1732, 2008.
View at: Publisher Site | Google Scholar
C. E. Brown, K. Aminoltejari, H. Erb, I. R. Winship, and T. H. Murphy, “In vivo voltage-sensitive dye imaging in adult mice reveals that somatosensory maps lost to stroke are replaced over weeks by new structural and functional circuits with prolonged modes of activation within both the peri-infarct zone and distant sites,” Journal of Neuroscience, vol. 29, no. 6, pp. 1719–1734, 2009.
View at: Publisher Site | Google Scholar
C. Calautti and J. C. Baron, “Functional neuroimaging studies of motor recovery after stroke in adults: a review,” Stroke, vol. 34, no. 6, pp. 1553–1566, 2003.
View at: Publisher Site | Google Scholar
R. M. Dijkhuizen, A. B. Singhal, J. B. Mandeville et al., “Correlation between brain reorganization, ischemic damage, and neurologic status after transient focal cerebral ischemia in rats: a functional magnetic resonance imaging study,” Journal of Neuroscience, vol. 23, no. 2, pp. 510–517, 2003.
View at: Google Scholar
P. Lipton, “Ischemic cell death in brain neurons,” Physiological Reviews, vol. 79, no. 4, pp. 1431–1568, 1999.
View at: Google Scholar
P. Nicotera and S. A. Lipton, “Excitotoxins in neuronal apoptosis and necrosis,” Journal of Cerebral Blood Flow and Metabolism, vol. 19, no. 6, pp. 583–591, 1999.
View at: Google Scholar
R. D. Schwartz, X. Yu, M. R. Katzman, D. M. Hayden-Hixson, and J. M. Perry, “Diazepam, given postischemia, protects selectively vulnerable neurons in the rat hippocampus and striatum,” Journal of Neuroscience, vol. 15, no. 1, pp. 529–539, 1995.
View at: Google Scholar
A. R. Green, A. H. Hainsworth, and D. M. Jackson, “GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke,” Neuropharmacology, vol. 39, no. 9, pp. 1483–1494, 2000.
View at: Publisher Site | Google Scholar
R. D. Schwartz-Bloom and R. Sah, “γ-aminobutyric acid A neurotransmission and cerebral ischemia,” Journal of Neurochemistry, vol. 77, no. 2, pp. 353–371, 2001.
View at: Publisher Site | Google Scholar
R. D. Schwartz-Bloom, K. A. Miller, D. A. Evenson, B. J. Crain, and J. V. Nadler, “Benzodiazepines protect hippocampal neurons from degeneration after transient cerebral ischemia: an ultrastructural study,” Neuroscience, vol. 98, no. 3, pp. 471–484, 2000.
View at: Publisher Site | Google Scholar
B. Alicke and R. D. Schwartz-Bloom, “Rapid down-regulation of GABA(A) receptors in the gerbil hippocampus following transient cerebral ischemia,” Journal of Neurochemistry, vol. 65, no. 6, pp. 2808–2811, 1995.
View at: Google Scholar
A. N. Clarkson, J. Clarkson, D. M. Jackson, and I. A. Sammut, “Mitochondrial involvement in transhemispheric diaschisis following hypoxia-ischemia: clomethiazole-mediated amelioration,” Neuroscience, vol. 144, no. 2, pp. 547–561, 2007.
View at: Publisher Site | Google Scholar
A. N. Clarkson, H. Liu, R. Rahman, D. M. Jackson, I. Appleton, and D. S. Kerr, “Clomethiazole: mechanisms underlying lasting neuroprotection following hypoxia-ischemia,” FASEB Journal, vol. 19, no. 8, pp. 1036–1038, 2005.
View at: Publisher Site | Google Scholar
M. D. Ginsberg, “Neuroprotection for ischemic stroke: past, present and future,” Neuropharmacology, vol. 55, no. 3, pp. 363–389, 2008.
View at: Publisher Site | Google Scholar
P. Lyden, A. Shuaib, K. Ng et al., “Clomethiazole acute stroke study in ischemic stroke (CLASS-I): final results,” Stroke, vol. 33, no. 1, pp. 122–128, 2002.
View at: Publisher Site | Google Scholar
L. Cohen, B. Chaaban, and M. O. Habert, “Transient Improvement of aphasia with zolpidem,” New England Journal of Medicine, vol. 350, no. 9, pp. 949–950, 2004.
View at: Publisher Site | Google Scholar
J. R. Inglefield, J. M. Perry, and R. D. Schwartz, “Postischemic inhibition of GABA reuptake by tiagabine slows neuronal death in the gerbil hippocampus,” Hippocampus, vol. 5, no. 5, pp. 460–468, 1995.
View at: Publisher Site | Google Scholar
D. J. Cash and K. Subbarao, “Two desensitization processes of GABA receptor from rat brain. Rapid measurements of chloride ion flux using quench-flow techniques,” FEBS Letters, vol. 217, no. 1, pp. 129–133, 1987.
View at: Google Scholar
J. R. Huguenard and B. E. Alger, “Whole-cell voltage-clamp study of the fading of GABA-activated currents in acutely dissociated hippocampal neurons,” Journal of Neurophysiology, vol. 56, no. 1, pp. 1–18, 1986.
View at: Google Scholar
M. H. J. Tehrani and E. M. Barnes Jr., “Agonist-dependent internalization of γ-aminobutyric acid(A)/benzodiazepine receptors in chick cortical neurons,” Journal of Neurochemistry, vol. 57, no. 4, pp. 1307–1312, 1991.
View at: Google Scholar
Y. Ben-Ari, R. Khazipov, X. Leinekugel, O. Caillard, and J. L. Gaiarsa, “GABA(A), NMDA and AMPA receptors: a developmentally regulated “menage a trois”,” Trends in Neurosciences, vol. 20, no. 11, pp. 523–529, 1997.
View at: Publisher Site | Google Scholar
M. M. McCarthy, A. P. Auger, and T. S. Perrot-Sinal, “Getting excited about GABA and sex differences in the brain,” Trends in Neurosciences, vol. 25, no. 6, pp. 307–312, 2002.
View at: Publisher Site | Google Scholar
C. Redecker, H. J. Luhmann, G. Hagemann, J. M. Fritschy, and O. W. Witte, “Differential downregulation of GABA(A) receptor subunits in widespread brain regions in the freeze-lesion model of focal cortical malformations,” Journal of Neuroscience, vol. 20, no. 13, pp. 5045–5053, 2000.
View at: Google Scholar
C. Redecker, W. Wang, J. M. Fritschy, and O. W. Witte, “Widespread and long-lasting alterations in GABAA-receptor subtypes after focal cortical infarcts in rats: mediation by NMDA-dependent processes,” Journal of Cerebral Blood Flow and Metabolism, vol. 22, no. 12, pp. 1463–1475, 2002.
View at: Google Scholar
M. Que, K. Schiene, O. W. Witte, and K. Zilles, “Widespread up-regulation of N-methyl-D-aspartate receptors after focal photothrombotic lesion in rat brain,” Neuroscience Letters, vol. 273, no. 2, pp. 77–80, 1999.
View at: Publisher Site | Google Scholar
A. Scimemi, A. Semyanov, G. Sperk, D. M. Kullmann, and M. C. Walker, “Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus,” Journal of Neuroscience, vol. 25, no. 43, pp. 10016–10024, 2005.
View at: Publisher Site | Google Scholar
S. J. Mitchell and R. A. Silver, “Shunting inhibition modulates neuronal gain during synaptic excitation,” Neuron, vol. 38, no. 3, pp. 433–445, 2003.
View at: Publisher Site | Google Scholar
R. M. McKernan and P. J. Whiting, “Which GABAA-receptor subtypes really occur in the brain?” Trends in Neurosciences, vol. 19, no. 4, pp. 139–143, 1996.
View at: Publisher Site | Google Scholar
M. Farrant and Z. Nusser, “Variations on an inhibitory theme: phasic and tonic activation of GABA_A receptors,” Nature Reviews Neuroscience, vol. 6, no. 3, pp. 215–229, 2005.
View at: Publisher Site | Google Scholar
N. C. Saxena and R. L. Macdonald, “Assembly of GABA(A) receptor subunits: role of the δ subunit,” Journal of Neuroscience, vol. 14, no. 11, pp. 7077–7086, 1994.
View at: Google Scholar
M. T. Bianchi and R. L. Macdonald, “Neurosteroids shift partial agonist activation of GABAA receptor channels from low- to high-efficacy gating patterns,” Journal of Neuroscience, vol. 23, no. 34, pp. 10934–10943, 2003.
View at: Google Scholar
S. Mertens, D. Benke, and H. Mohler, “GABAA receptor populations with novel subunit combinations and drug binding profiles identified in brain by α5- and δ-subunit-specific immunopurification,” Journal of Biological Chemistry, vol. 268, no. 8, pp. 5965–5973, 1993.
View at: Google Scholar
A. Baude, C. Bleasdale, Y. Dalezios, P. Somogyi, and T. Klausberger, “Immunoreactivity for the GABAA receptor α1 subunit, somatostatin and connexin36 distinguishes axoaxonic, basket, and bistratified interneurons of the rat hippocampus,” Cerebral Cortex, vol. 17, no. 9, pp. 2094–2107, 2007.
View at: Publisher Site | Google Scholar
C. Sun, W. Sieghart, and J. Kapur, “Distribution of α1, α4, γ2, and δ subunits of GABAA receptors in hippocampal granule cells,” Brain Research, vol. 1029, no. 2, pp. 207–216, 2004.
View at: Publisher Site | Google Scholar
D. W. Cope, P. Wulff, A. Oberto et al., “Abolition of zolpidem sensitivity in mice with a point mutation in the GABAA receptor γ2 subunit,” Neuropharmacology, vol. 47, no. 1, pp. 17–34, 2004.
View at: Publisher Site | Google Scholar
J. Liepert, “Motor cortex excitability in stroke before and after constraint-induced movement therapy,” Cognitive and Behavioral Neurology, vol. 19, no. 1, pp. 41–47, 2006.
View at: Publisher Site | Google Scholar
A. Floyer-Lea, M. Wylezinska, T. Kincses, and P. M. Matthews, “Rapid modulation of GABA concentration in human sensorimotor cortex during motor learning,” Journal of Neurophysiology, vol. 95, no. 3, pp. 1639–1644, 2006.
View at: Publisher Site | Google Scholar
R. M. Lazar, B. F. Fitzsimmons, R. S. Marshall et al., “Reemergence of stroke deficits with midazolam challenge,” Stroke, vol. 33, no. 1, pp. 283–285, 2002.
View at: Publisher Site | Google Scholar
J. P. van der Zijden, P. van Eijsden, R. A. De Graaf, and R. M. Dijkhuizen, “1H/13C MR spectroscopic imaging of regionally specific metabolic alterations after experimental stroke,” Brain, vol. 131, no. 8, pp. 2209–2219, 2008.
View at: Publisher Site | Google Scholar
C. M. Stinear, J. P. Coxon, and W. D. Byblow, “Primary motor cortex and movement prevention: where Stop meets Go,” Neuroscience and Biobehavioral Reviews, vol. 33, no. 5, pp. 662–673, 2009.
View at: Publisher Site | Google Scholar
J. W. Stinear and W. D. Byblow, “Disinhibition in the human motor cortex is enhanced by synchronous upper limb movements,” Journal of Physiology, vol. 543, no. 1, pp. 307–316, 2002.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2012 Andrew N. Clarkson. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

3049

Downloads

1690

Citations