Once a blood vessel supplying the brain has been blocked, the opportunity to prevent brain damage is fleeting. An alternative strategy might be to guide the damaged area onto the path to recovery. See Letter p.305
The old saying that 'timing is everything' certainly applies to the treatment of strokes — the devastating injuries caused by obstructions to blood flow in the vessels that supply the brain. Advances in removing such obstructions have led to dramatic ameliorations in stroke damage. Unfortunately, however, restoring blood flow is beneficial only if achieved within the first few hours of obstruction: most patients still endure the full brunt of the injury. As a result, a rapidly expanding area of research is focused on enhancing the recovery from this damage, which is considerably less time-critical1. On page 305 of this issue, Clarkson and colleagues2 report that recovery from a stroke is significantly improved when neuronal inhibition is reduced, starting three days after the injury.
Recovery of function after a stroke involves substantial alterations in the connectivity of the neurons that formerly interacted with the injured area3. Not surprisingly, many of these neurons are found in the brain regions immediately adjacent to the injury — the peri-infarct zone. A key regulator of the plasticity of synaptic connections is the inhibitory system subserved by the neurotransmitter GABA4. Clarkson et al. measured in vitro the currents mediated by GABA in mouse neurons of the peri-infarct zone, starting their measurements three days after a stroke. They found that the fast synaptic signalling mediated by GABA was normal, but that the background activity (referred to as tonic inhibition) was significantly increased in the peri-infarct zone.
Tonic inhibition operates through GABAA receptors, which are distributed between synapses to increase the permeability of the neurons' membrane to anions. This increase in the electrical leakiness of the neuronal membrane short-circuits the excitatory signals conducted from synaptic inputs to the cell body and to the axon hillock — the site at which action potentials are generated. The GABA that activates these extrasynaptic receptors arises from spill-over at active synapses. GABA transporters normally return this GABA to both astrocytes and neurons (Fig. 1). But when neurons are depolarized, the transporters can function in reverse, causing extracellular GABA to increase.
GABA transporters might also function in reverse near the injured zone, as a secondary consequence of excessive activation of glutamate receptors or compromised energy production5. But when Clarkson et al.2 blocked these transporters, they observed a robust increase in the GABA-mediated tonic conductance, suggesting that in the peri-infarct zone GABA transporters decrease — rather than increase — the extracellular GABA concentration.
There are several molecular species of GABA transporter. On sequential blocking of the transporters with selective pharmacological antagonists, the authors found that the GAT-1 transporter functions normally in the peri-infarct zone, whereas GABA uptake by the GAT-3 transporters is reduced (Fig. 1). They also report that a selective decrease in GAT-3 expression — and so not a change in the ionic conditions that drive uptake — is associated with changes in GABA uptake, increasing tonic inhibition in the peri-infarct zone.
Seizures, which can be caused by reduced inhibition, complicate 5% of the acute strokes that occur in the cortex region of the brain6. So an increase in tonic inhibition in the peri-infarct zone might be protective. But Clarkson et al. reasoned that such protection might come at the cost of reduced ability to alter synaptic connections4 — a process essential for functional remapping of the cerebral cortex. Instead, reducing neural inhibition might enhance the processes of plasticity by which cortical regions are altered to improve muscle control. Indeed, the authors find that reducing tonic inhibition improves motor recovery after stroke, as evidenced by the number of missteps rats take while walking along a suspended wire grid.
Furthermore, Clarkson and co-workers present two independent lines of evidence to show that reducing tonic inhibition improves functional recovery after a stroke. In one set of experiments, the authors studied mice lacking two GABA-receptor subunits that are found primarily in extrasynaptic receptors and so mediate tonic inhibition. In another set, they used an antagonist that specifically targets these subunits to selectively reduce GABA-mediated tonic inhibition. In both cases, the outcome was improved post-stroke recovery of locomotor function.
These intriguing observations2 open many research avenues. First and foremost is safety: because of the incidence of seizures after stroke6, the risks of reducing GABA-mediated tonic inhibition must be carefully assessed. The source of the increased tonic GABA conductance in the peri-infarct zone also warrants further investigation; pharmacological removal of GAT-3 in the healthy neocortex does not alter tonic inhibition7.
Again, timing is everything: previous work8 indicated that increased inhibition at the time of the stroke is beneficial. In addition, when Clarkson et al. reduced inhibition too soon after the stroke, they observed a detrimental effect — increase in stroke size. These timing constraints point to overlapping beneficial and detrimental GABA functions and need to be resolved.
Clarkson and colleagues' experimental reductions of GABA-mediated tonic inhibition affected the entire brain, leaving uncertainty as to whether the enhanced tonic inhibition in the peri-infarct zone was the main site of action. Strokes alter the activity of local networks in which the injured zone was involved9. Consequently, both local and general alterations in inhibition might help to reconstitute some of these network activities10 and so improve functional recovery.
All of the benefits that Clarkson et al. report for reducing GABA-mediated inhibition had occurred by the time of their first assay of functional recovery — one week after the stroke. Thereafter, both treated and untreated animals recovered at the same rate. This result again raises the possibility that a reduction in GABA-mediated tonic inhibition improves the function of the damaged cortical networks, as opposed to enhancing the long-term recovery of those networks. The latter would increase the rate of improvement in gait, and would persist after the GABA blockers are removed. Of course, it could be that both effects (improvements in immediate function as well as recovery) contribute to the observed improvements in muscle control: Clarkson and co-workers show that discontinuation of GABA blockade removes about half of the improvement in recovery.
Reducing GABA-mediated inhibition enhances alertness. Although Clarkson et al. rule out an immediate performance enhancement by treating a subgroup of animals just before each test, stimulants are known to improve stroke recovery in rodents11, if not humans. So future work should carefully control for effects of GABA manipulations on the level of consciousness.
Strategies to accelerate recovery from stroke not only offer a possible complement to the emergency rescue strategies, but are also much more feasible: they can be used at later times after a stroke. The present study2 promises one such strategy, subject to further investigation.
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Expert Review of Neurotherapeutics (2012)