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Extrasynaptic GABAA Receptors pp 179–205Cite as

The Role of Peri-synaptic GABA Receptors After Stroke

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Part of the book series: The Receptors ((REC,volume 27))

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.

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Authors and Affiliations

  1. Departments of Anatomy and Psychology, University of Otago, PO Box 913, 9013, Dunedin, New Zealand

    Andrew N. Clarkson

  2. Department of Pharmacy A15, University of Sydney, Sydney, NSW, Australia

    Mary Chebib

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  1. Andrew N. Clarkson
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  2. Mary Chebib
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Correspondence to Andrew N. Clarkson .

Editor information

Editors and Affiliations

  1. Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, United Kingdom

    Adam C. Errington

  2. Dept. of Physiology & Biochemistry, University of Malta, Msida MSD, Malta

    Giuseppe Di Giovanni

  3. School of Biosciences, Cardiff University, Cardiff, United Kingdom

    Vincenzo Crunelli

Conclusions

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 (Krakauer 2006) that indicate learning and memory principles may underlie behavioral recovery. The idea that certain aspects of learning and memory rules and changes in neuronal excitability can alter the profile of recovery after a stroke has led to ad hoc attempts to treat patients with any available drug known to stimulate learning and memory, such as amphetamine, dopamine agonists, and methylphenidate, to name just a few. As these compounds work through multiple receptor systems in the brain and were designed to treat neurological conditions other than being a neurorehabilitative aid, they have failed to translate into the clinic (Berends et al. 2009). At the cellular level, learning and memory principles are mediated by specific excitatory neuronal responses, such as LTP, and are potentiated by drugs that facilitate aspects of excitatory neuronal signaling (Walker and Semyanov 2008), such as tonic GABAAR antagonists (Glykys and Mody 2007a). Recent data show 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 (see Fig. 9.6). These effects occur through blockade of α5- or δ-containing GABAARs. These data indicate a novel role for tonic GABAAR function in promoting poststroke recovery most likely via cortical disinhibition (Jacobs and Donoghue 1991; Stinear et al. 2009; Stinear and Byblow 2002) and suggest 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.

Fig. 9.6
figure 6

Schematic summary of key changes in tonic GABA and stroke recovery. Stroke increases peri-infarct GABA by reducing the level of the GABA transporter, GAT-3/4, indicated by lighter shading in a subset of GAT-3/4 (blue pinwheels). The function and the level of GAT-1 are unaltered (orange pinwheels). Due to different subunit-associated properties, extrasynaptic GABAARs (green) mediate a tonic form of inhibition that is distinct from the phasic form mediated by synaptic GABAARs (orange).Tonic inhibitory currents in peri-infarct pyramidal neurons (red trace) are increased compared to control neurons (blue trace). Reducing tonic inhibition with a selective α5-GABAAR inverse agonist (L655,708) reverses the increase in tonic inhibition and improves behavioral recovery in forelimb motor control after stroke

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Acknowledgments

This manuscript was completed during tenure of a Sir Charles Hercus Fellowship from the Health Research Council of New Zealand.

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Clarkson, A., Chebib, M. (2014). The Role of Peri-synaptic GABA Receptors After Stroke. In: Errington, A., Di Giovanni, G., Crunelli, V. (eds) Extrasynaptic GABAA Receptors. The Receptors, vol 27. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1426-5_9

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