A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke

Abstract

Stroke causes loss of neurological function. Recovery after stroke is facilitated by forced use of the affected limb and is associated with sprouting of new connections, a process that is sharply confined in the adult brain. We show that ephrin-A5 is induced in reactive astrocytes in periinfarct cortex and is an inhibitor of axonal sprouting and motor recovery in stroke. Blockade of ephrin-A5 signaling using a unique tissue delivery system induces the formation of a new pattern of axonal projections in motor, premotor, and prefrontal circuits and mediates recovery after stroke in the mouse through these new projections. Combined blockade of ephrin-A5 and forced use of the affected limb promote new and surprisingly widespread axonal projections within the entire cortical hemisphere ipsilateral to the stroke. These data indicate that stroke activates a newly described membrane-bound astrocyte growth inhibitor to limit neuroplasticity, activity-dependent axonal sprouting, and recovery in the adult.cortical map | regeneration | repair | motor function | EphA4

Emergent properties of neural repair: elemental biology to therapeutic concepts

“…In both the cortex contralateral to the stroke, and ipsilateral or peri‐infarct cortex, animal models indicate that axonal sprouting establishes new patterns of connections that are causally linked to recovery. In peri‐infarct cortex, when new connections are stimulated from motor to premotor cortex motor recovery is enhanced, and when these same connections are blocked from forming motor recovery is reduced 13, 33. In contralateral cortex, when new connections form in the cervical spinal cord, reaching into the portion of the cervical spinal cord that has lost its original projection from the stroke site, this process mediates part of the motor recovery in a rat stroke model 29.…”

“…Axonal connections are confined by the expression of glial growth inhibitory molecules, such as NogoA, EphrinA5, and chondroitin sulfate proteoglycans 11, 12, 27, 28, 29, 30, 31, 32, 33. Opposed to these glial growth inhibitors, sprouting neurons activate a unique regenerative molecular program 11, 12, 13.…”

“…Opposed to these glial growth inhibitors, sprouting neurons activate a unique regenerative molecular program 11, 12, 13. Outside of stroke, behavioral activity in the normal adult brain, such as overuse or learning in a forelimb task, induces local changes in synaptic connections on a small scale within the corresponding motor cortex 33, 40, 41. However, when the behavioral activity patterns of neurorehabilitative therapy are added to the axonal sprouting response in stroke, emergent properties appear that are not present in either of these 2 parent conditions.…”

“…Stroke induces axonal sprouting in motor, somatosensory, and premotor areas in peri‐infarct cortex. When glial growth inhibitors are blocked after stroke, this axonal sprouting response is locally enhanced in these cortical areas 11, 33. When glial growth inhibitors are blocked and the animal is forced to overuse the affected forelimb, a model for the clinical approach of constraint‐induced motor therapy, there is a magnitude of axonal sprouting that is remarkable in the adult brain.…”

“…When glial growth inhibitors are blocked and the animal is forced to overuse the affected forelimb, a model for the clinical approach of constraint‐induced motor therapy, there is a magnitude of axonal sprouting that is remarkable in the adult brain. New projections are formed from motor cortex to widespread areas in prefrontal, orbitofrontal, temporal, and parietal cortical areas in a substantial remapping of the ipsilateral hemisphere 33. The magnitude and pattern of axonal sprouting that are seen when behavioral activity is modified under conditions of manipulation of glial growth inhibitors emerge as unique, widespread, and unpredictable from the 2 individual conditions that underlie this response: behavioral activity alone and glial growth inhibition blockade alone 40.…”