Loss of GABAB-mediated interhemispheric synaptic inhibition in stroke periphery

Abstract

Recovery after stroke is mediated by plastic changes largely occurring in the lesion periphery. However, little is known on the microcircuit changes underlying recovery, at which extent perilesional plasticity occurs at synaptic input vs. spike output level, and on the connectivity behind such synaptic plasticity. We combined intrinsic imaging with extra- and intra-cellular 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 of neighboring forelimb area (fS1), suggesting that in normal conditions they originate via horizontal connections from neighboring 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 GABA_B receptors were antagonized in the recorded area. Conversely, such GABA_B-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 due to a pathway-specific facilitatory action on the affected sensory response from contralateral cortex.

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