THE ROLE OF THE SVZ IN ISCHEMIC CONDITION

Abstract

The occlusion of a cerebral artery or stroke often results in neuronal deficit and/or patient death. A partial recovery often follows non-fatal stroke and this may be due to the activation of the progenitor cells in the Sub- Ventricular Zone (SVZ) naturally occurring after ischemia. In order to clarify the role of the SVZ neurogenesis in animal recovery, the effect of neurogenesis inhibition and boosting were studied in the mouse Middle Cerebral Artery occlusion model (MCAo). 6 to 10-week-old male mice were pre-treated with intracranial injections of lentiviral vector (LV) or integration deficient lentiviral vectors (IDLV), in order to target the SVZ. The IDLV carried an expression cassette encoding for a precursor Glial cell-derived neurotrophic factor (GDNF) or the tetanus toxin fragment C (TTC), which recently has been demonstrated to have growth factor like behaviour. Another group of animals received the LV carrying a double promoter expression cassette encoding for an eGFP, and in order to inhibit the cell cycle in targeted cells the shRNA_Cyclin D1. All vectors were co-injected with the LV_ pHR’SIN-cPPT-SEW, which contains an eGFP cassette. Two weeks later the animals received the MCAo, and for three weeks the sensorimotor behaviour was tested. Neurological assessment showed the sensory-motor debilitation was significant increased after the treatment with the LV_shRNA_CyclinD1 (* p<0.05); the IDLV_GDNF and IDLV_TTC groups showed a trend to improve neurological deficit in the subjects alive until day 5. In the IDLV_GDNF, the SVZ’s derived green cells were positively correlated with the ischemic volume, *p<0.05 R=0.68, and the neurodegeneration, ***p<0.001 R=0.92. Moreover, while the SVZ neurogenesis inhibition reduced life expectancy, the boosting significantly improved it. Immunofluorescence analysis showed a migration extended to the striatum and cortex with a max distance of 1.87 mm from the SVZ.