Research Article: Perisynaptic GABA Receptors The Overzealous Protector

Date Published: February 22, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Andrew N. Clarkson.

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

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 GABAA receptors and spillover onto perisynaptic GABAA 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.

Partial Text

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 GABAA, GABAB, and GABAC receptors [2], and these receptor subtypes have been classified according to differences in both structure and pharmacology. GABAARs 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 GABAAR subunits exist: α1–6, β1–3, γ1–3, δ, ε, φ, π, and ρ1–3, 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].

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 GABAAR 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 GABAAR modulator, can result in transiently improves in aphasia in chronic stroke survivors [68].

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.

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 GABAAR 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].

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 GABAAR 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 GABAAR’s. This data indicates a novel role for tonic GABAAR 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.

 

Source:

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

 

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