Ischemic stroke triggers brain-wide synaptic remodeling within four hours

TL;DR

Ischemic stroke causes rapid brain-wide changes in synapses, with loss in the damaged area and increased activity in the opposite side of the brain.

Contribution

The study reveals region-specific synaptic remodeling in the hyperacute phase of stroke, including functional enhancement in the contralateral cortex.

Findings

Synapses in the ischemic core are rapidly lost within four hours of stroke.

The contralateral cortex shows increased synaptic staining and vesicle cycling.

Blocking NMDA receptors worsens synaptic decline in the penumbra and prevents contralateral synaptic increase.

Abstract

Physiological mechanisms of the key hyperacute (0–24 hours) stage of stroke are poorly understood, hampering the development of new therapies. Synaptic plasticity has been strongly implicated in early stages of neurodegenerative and neurodevelopmental disorders, yet its relevance in early stroke remains unclear. Here, we describe the emergence of distinct region-specific forms of synaptic remodeling following middle cerebral artery occlusion in rats, arising within the critical 4-hour period. Synapses within the severely ischemic core region were rapidly lost, while those in the mildly ischemic penumbra, albeit largely structurally intact, were functionally diminished. In contrast, the contralateral cortex exhibited increased synaptic staining and synaptic vesicle cycling. Systemic pharmacological blockade of NMDA-type glutamate receptors abolished contralateral synaptic increase and exacerbated synaptic decline in the penumbra. Proteomic and transcriptomic analyses showed that cross-brain synaptic plasticity is independent of local gene expression and revealed metabolic rearrangement and synaptic downregulation in the penumbra. These findings identify brain-wide synaptic rebalancing as a potential mechanism for rapid functional compensation in hyperacute stroke, highlighting the extent of brain response to acute perturbation.

Ischemic stroke induces substantial neuronal remodeling, which is often studied in the context of mid-to-long term functional rehabilitation. This study characterizes early synaptic remodeling in a mouse model of stroke, revealing a loss of synapses in the ischemic core, but functional enhancement of synapses in the contralateral cortex.

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