THE ROLE OF THE SVZ IN ISCHEMIC CONDITION

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.