Abstract WP236: Tet3 Overexpression Improves Functional Recovery In Male And Female Mice Following Focal Ischemia

Abstract

Epigenetic mechanisms have been shown to play a major role in the progression of stroke pathophysiology. The ten eleven translocases (TETs) are enzymes involved in generating DNA hydroxymethylcytosine (5hmC), a brain enriched epigenetic modification that is associated with transcriptional activation and neuroprotection. We have previously shown that the TET3 isoform may be involved in promoting endogenous neuroprotective pathways following brain injury. In the current study, we investigated the role of TET3 activity after stroke by examining functional recovery, neuroprotection, and sex-specific differences after TET3 modulation. Adult C57BL6/J mice were subjected to transient middle cerebral artery occlusion (MCAO) to induce focal cerebral ischemia. Dot blotting analysis revealed robust induction of 5hmC levels from 1 hour to 24 hours of reperfusion in the mouse cortex. Intracerebral injection of a neuronal-specific TET3 adenovirus further enhanced TET activity and 5hmC levels in both male and female mice. Overexpression of TET3 led to decreased infarct volume and edema and improved neurological scores at 24 hours of reperfusion. Furthermore, both male and female mice subjected to a battery of motor function assessments from 3 days to 14 days of reperfusion displayed enhanced motor function recovery with increased TET3. These results indicate that TET3-mediated epigenetic regulation may hold therapeutic potential following cerebral ischemia.