Loss of GABAB -mediated interhemispheric synaptic inhibition in stroke periphery.

ABSTRACT

KEY POINTS Recovery from the potentially devastating consequences of stroke depends largely upon plastic changes occurring in the lesion periphery and its inputs. In a focal model of stroke in mouse somatosensory cortex, we found that the recovery of sensory responsiveness occurs at the level of synaptic inputs, without gross changes of the intrinsic electrical excitability of neurons, and also that recovered responses had longer than normal latencies. Under normal conditions, one somatosensory cortex inhibits the responsiveness of the other located in the opposite hemisphere (interhemispheric inhibition) via activation of GABAB receptors. In stroke-recovered animals, the powerful interhemispheric inhibition normally present in controls is lost in the lesion periphery. By contrast, contralateral hemisphere activation selective contributes to the recovery of sensory responsiveness after stroke. ABSTRACT Recovery after stroke is mediated by plastic changes largely occurring in the lesion periphery. However, little is known about the microcircuit changes underlying recovery, the extent to which perilesional plasticity occurs at synaptic input vs. spike output level, and the connectivity behind such synaptic plasticity. We combined intrinsic imaging with extracellular and intracellular recordings and pharmacological inactivation in a focal stroke in mouse somatosensory cortex (S1). In vivo whole-cell recordings in hindlimb S1 (hS1) showed synaptic responses also to forelimb stimulation in controls, and such responses were abolished by stroke in the neighbouring forelimb area (fS1), suggesting that, under normal conditions, they originate via horizontal connections from the neighbouring fS1. Synaptic and spike responses to forelimb stimulation in hS1 recovered to quasi-normal levels 2 weeks after stroke, without changes in intrinsic excitability and hindlimb-evoked spike responses. Recovered synaptic responses had longer latencies, suggesting a long-range origin of the recovery, prompting us to investigate the role of callosal inputs in the recovery process. Contralesional S1 silencing unmasked significantly larger responses to both limbs in controls, a phenomenon that was not observed when GABAB receptors were antagonized in the recorded area. Conversely, such GABAB -mediated interhemispheric inhibition was not detectable after stroke callosal input silencing failed to change hindlimb responses, whereas it robustly reduced recovered forelimb responses. Thus, recovery of subthreshold responsiveness in the stroke periphery is accompanied by a loss of interhemispheric inhibition and this is a result of pathway-specific facilitatory action on the affected sensory response from the contralateral cortex.