Synapse Loss and Regeneration: A Mechanism for Functional Decline and Recovery after Cerebral Ischemia?

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Abstract
Little is known of the mechanisms governing functional recovery after ischemic brain injury, and there is no clinical therapy established to restore neurologic function after ischemic injury is complete. Even so, pronounced spontaneous recovery of function is often observed in a subset of patients. Resolution of neurological deficits after ischemia must occur through replacement of lost tissue via production of new neurons, or through changes in the structure, function, or connectivity of surviving neurons. This review focuses on the neuronal synapse as a potential locus for functional recovery. Selective disruption of synaptic elements is a characteristic feature of hypoxic-ischemic brain injury, such as that seen in ischemic stroke or cardiac arrest. Ischemic damage to synapses occurs even in the absence of neuronal loss, and therefore might underlie the clinical disability observed in patients following mild or transient ischemia. We review evidence that recovery of lost synapses occurs after ischemic injury and that this recovery may be a necessary step for restoration of neurological function. The process of synapse loss and recovery can be examined in neuronal cultures and experimental stroke models. Such studies may help to gain a better understanding of the extracellular factors and intracellular cascades that facilitate recovery of synapses, and may result in therapeutic approaches to improve function after cerebral ischemia.