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. 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 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: , , , 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 GABAAR’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 GABAAR’s in the hippocampus and cortex contain either
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