Stroke Therapy
GABA & Neural Repair

Ischemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Thus, elucidating mechanisms that promote this plasticity is critical for the development of new stroke therapeutics with a broad treatment window.

GABA signaling is a critical component in the development and plasticity of cortical map boundaries in the normal brain and may also mediate the stroke-induced cortical remapping required for functional recovery. Indeed, a role for GABA in plasticity-related recovery was suggested by Clarkson et al. (Nature, 2010) who demonstrated that tonic GABA signaling (governed by extrasynaptic GABAA receptors) during the repair phase was detrimental to stroke recovery in mice.

Phasic (also known as ‘synaptic’) GABA signaling is the classical mode of GABA signaling mediated, largely, by GABAA receptors at the synapse. While enhancing phasic GABA is known to be neuroprotective and reduce excitotoxic neuron death in the acute phase of stroke (i.e. within hours of stroke onset), its role in plasticity-related recovery during the repair phase of stroke is largely unknown, although the general assumption was that it would also be detrimental. To test this we used a combined approach of array tomography, a high resolution proteomic imaging method, and electrophysiology and found increased numbers of GABA synapses after stroke and increased post-synaptic phasic GABA signaling specific to cortical layer 5 pyramidal neurons (GABA Figures 1 & 2)( eg., Steinberg et al Brain 2015) This increase was transient observed one week after stroke but returning to baseline levels by 1 month. To determine the effect of this increased phasic signaling on stroke recovery we further enhanced phasic GABA signaling in the repair phase of stroke, using the FDA-approved GABA modulator zolpidem. Instead of being detrimental, we found that phasic GABA signaling in the repair phase of stroke is actually beneficial and enhanced post-stroke recovery in mice, without being neuroprotective (GABA Figures 3).

Figure 1: GABA synapse density is significantly increased in the peri-infarct at one week post-stroke in cortical layer 5 but not 2/3.

Figure 2: (A, B) sIPSC recordings from representative layer 5 pyramidal neurons from (A) control and (B) stroke-injured mice showing a larger response in the latter. (C) Ensemble-averaged IPSCs from pyramidal cells at 1 week post-stroke showing the average charge (area under the curve) of sIPSCs in layer 5 pyramidal neurons is increased in stroke-injured mice.

Figure 3: Enhancing phasic GABA signaling using low dose zolpidem treatment starting in the repair phase at day 3 after stroke, enhances functional recovery.

Significance: These data establish a novel and unexpected role for phasic GABA signaling in enhancing plasticity-related recovery after stroke injury. This highlights the necessity to distinguish between the role of phasic and tonic GABA inhibition in brain repair. We believe this will establish a paradigm shift in the current understanding of GABA signaling in post-stroke brain recovery.

Our data identify a new mechanism involved in brain recovery and thus offer a new therapeutic strategy for stroke, with the possibility of zolpidem as a pharmacological agent to treat stroke in the repair phase. As zolpidem is an FDA-approved sleep aid, better known as Ambien, it offers the potential of a tested and safe pharmacological agent for stroke treatment. Of note, several case reports suggest that zolpidem can improve recovery after brain injury in patients. It remains to be determined what circuits are being altered by zolpidem treatment to affect recovery.