Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke

Abstract

Stroke is a leading cause of disability; but no pharmacological therapy is currently available for promoting recovery. The brain region adjacent to stroke damage, the peri-infarct zone, is critical for rehabilitation, as it exhibits heightened neuroplasticity, allowing sensorimotor functions to re-map from damaged areas1–3. Thus, understanding the neuronal properties constraining this plasticity is important to developing new treatments. Here we show that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone. This increased tonic inhibition is mediated by extrasynaptic GABAA receptors (GABAARs) and is caused by an impairment in GABA transporter (GAT-3/4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for the α5-subunit-containing extrasynaptic GABAARs at a delay after stroke. This treatment produced an early and sustained recovery of motor function. Genetically lowering the number of α5 or δ-subunit-containing GABAARs responsible for tonic inhibition also proved beneficial for post-stroke recovery, consistent with the therapeutic potential of diminishing extrasynaptic GABAAR function. Together, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries.

Emergent properties of neural repair: elemental biology to therapeutic concepts

“…In stroke, tonic GABA signaling is increased in peri‐infarct cortex in a zone of cortex near the stroke site (0.2mm adjacent to the stroke) and produces a hypoexcitable state in pyramidal neurons in brain regions that normally mediate recovery of function. This can be pharmacologically reversed to enhance recovery in several rodent models of stroke at a considerable delay after the infarct 5, 47…”

“…No technique in human studies (theta burst magnetic stimulation [TMS], transcranial direct current stimulation [tDC], magnetic resonance imaging [MRI] positron emission tomography) can specifically measure tonic and not phasic inhibition 50. Perhaps the closest ability to replicate the findings behind the mechanism of increased tonic GABA inhibition in a human study would be in measuring total extrasynaptic GABA levels, which in the mouse are elevated because of reduced astrocyte uptake of GABA after stroke 5. However, the only ability to measure GABA in humans is with [18]F‐flumazenil (which measures synaptic GABA receptor binding occupancy) and GABA magnetic resonance spectroscopy MRI (which measures total GABA levels in a 2 × 2 mm block of brain tissue).…”

“…tDC and TMS are methods to do this in humans. Unlike the pharmacological manipulation of tonic GABA in rodent models of stroke, which specifically manipulate excitatory neurons and preferentially those that have been impacted by stroke,5 tDC and TMS more grossly affect all of the brain tissue in the electrical or magnetic field, and induce many distinct types of cortical circuits 55. Nonetheless, small‐scale studies indicate that excitatory tDC or TMS over the ipsilesional hemisphere in stroke, or inhibitory tDC over the contralateral hemisphere, may improve recovery after stroke 55.…”

“…In studies with blocking tonic GABA signaling or enhancing signaling through the AMPA glutamate receptor, when therapy was within 3 to 5 days from the stroke, GABA antagonists or AMPA drugs make the stroke worse by increasing infarct size. When these therapies are initiated after this 3‐ to 5‐day period, they do not change infarct size and enhance motor recovery 5, 60. Many neural repair therapies enhance endogenous neuronal plasticity in ways that activate neuronal excitability, such as with enhancing signaling of the transcription factor Creb,61 and might be expected to also follow this timeline.…”

“…Each of these cellular events is a distinct and definable property of the brain tissue response to stroke, and has irreducible elements in its response. For example, reactive astrocytes downregulate the uptake of the inhibitory transmitter γ‐aminobutyric acid (GABA), and this causes an elevation in tonic GABA signaling and hypoexcitability of pyramidal neurons adjacent to stroke 5. In poststroke neurogenesis, angiogenic vessels release chemokines and growth factors that simulate immature neurons to migrate to areas of brain injury adjacent to the stroke core 6, 7, 8.…”