Perisynaptic GABA Receptors: The Overzealous Protector

Andrew N Clarkson

doi: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.

Highlights

Using pharmacological and genetic manipulations of extrasynaptic GABAAR’s, we have shown marked improvements in functional recovery when starting treatments from 3 days after the stroke [21]
Therapies that promote functional recovery after stroke are limited to physical rehabilitation measures
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]

Summary

GABA and Cerebral Ischemia

A large body of work has been devoted to developing and exploring neuroprotectants that act to block glutamatemediated neurotransmission in animal models of cerebral ischemia [57, 58]. The GABAAR is 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]. 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 GABAAR’s resulting in an increase in tonic inhibition. 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. 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

Poststroke Tonic Inhibition

Dampening Cortical Inhibition Alters Cortical Responsiveness

Findings

Conclusions