Rac1 activity changes are associated with neuronal pathology and spatial memory long-term recovery after global cerebral ischemia

Excitotoxicity is the main event during neurological disorders producing drastic morphological and functional changes. Rac-GTPase is involved in cytoskeletal remodeling and survival. However, the role of Rac1 after cerebral ischemia has not been completely understood yet. In this study, we evaluated the activity of Rac1 and its immunoreactivity associated to neuropathological hallmarks and behavioral task analyses after global cerebral ischemia in an acute and long-term post-ischemia period. Our findings showed that during the acute phase (24 h) after global cerebral ischemia, a decrease of the active state of Rac1 was detected in the hippocampus, together with a down-regulation of survival signaling. In this same post-ischemia time, Rac1 immunoreactivity was redistributed to cytoplasm and to aberrant neurites, accompanied by dendritic and actin cytoskeletal retraction both in vivo and in vitro in neuronal primary cultures treated with glutamate. Neurons transfected with the constitutively active mutant of Rac1 were recovered from the glutamate-induced affection in vitro. However, in the in vivo model an inactive state of Rac1, and its cellular localization remained one month after ischemia, with still decreased survival signaling, significant tauopathy, and learning and memory alterations. These neuropathological hallmarks were reversed two months post-ischemia,related with a Rac1 activity state similar to control, as well as a “normalization” of the learning and memory tasks in the ischemic rats. In summary, our data suggests that changes in Rac1 activity are involved in the neurodegenerative processes after cerebral ischemia, and also in its long-term recovery.

Research highlights▶ Cerebral ischemia produced translocation of inactive Rac1 to the neuronal cytoplasm. ▶ Inactive Rac1 in soma was present in tauopathy and memory deficit after ischemia. ▶ Changes in the activity of Rac1 are involved in the long-term recovery after cerebral ischemia. ▶ Rac1 is a molecular pivot and convergent target of neuronal survival and plasticity pathways.