The Role of Peri-synaptic GABA Receptors After Stroke

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 remains the second leading cause of death and is the leading cause of lasting adult disability worldwide. Stroke-induced cell death occurs due to an excess release of glutamate. As a consequence to this, a compensatory increased release of γ-aminobutyric acid (GABA) occurs that results in the subsequent internalization of synaptic GABAA receptors and spillover onto peri-synaptic/extrasynaptic GABAA receptors, resulting in an increase in 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. The central cellular process in these events is alteration in neuronal response to incoming inputs—manipulations that increase neuronal firing to a given input are likely to induce changes in neuronal structure and alterations in cortical maps. 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 from 3 days poststroke can afford an early and robust improvement in functional recovery after stroke. Further, recent data also suggest that boosting tonic GABA inhibition early after a stroke can afford significant protection and minimize the extent of neuronal cell loss.KeywordsCortical excitabilityDisinhibitionNeuroprotectionNeurorepairPlasticity