Abstract W P92: Attenuated GFAP/Vimentin Retards Motor Behavioral Recovery and Axonal Remodeling and Up-regulates Axonal Growth-Inhibiting Molecules in Mice After Stroke

Abstract

To investigate whether reactive astrocytes contribute to neurological recovery, we compared behavioral outcome, axonal remodeling of the corticospinal tract (CST) and the levels of axonal growth-inhibiting/promoting molecules in the central nervous systems (CNS) between wild-type (WT) and glial fibrillary acidic protein/vimentin double knockout (GFAP-/-Vim-/-) mice subjected to Rose Bengal induced cerebral cortical photothrombotic stroke in the right forelimb motor area. Both foot-fault test and single pellet reaching test were performed prior to stroke and at 3 days after stroke and weekly thereafter, to monitor functional deficit and recovery. Biotinylated dextran amine (BDA) was injected into the left motor cortex to label the CST axons anterogradely. Compared with WT mice, the motor functional recovery and BDA-positive CST axonal length in the denervated side of the cervical gray matter were significantly reduced in GFAP-/-Vim-/-mice (n=10/group, P<0.01). Western blot data (prior to and on 3, 7 or 14 days after stroke, n=6/group) showed that in GFAP-/-Vim-/- mice, axonal growth-inhibiting molecules, Nogo R and neurocan, were up-regulated time-dependently in the CNS compared with WT mice (P<0.01). However, no increase was detected in the expressions of Nogo A and Oligodendrocyte myelin glycoprotein (P>0.05). There was no difference in the levels of axonal growth-promoting molecules (Myelin-Associated Glycoprotein and phosphor-ERK) between GFAP-/-Vim-/-mice and WT littermates (p>0.05). Our results suggest that attenuated astrocytic reactivity impairs or delays neurological recovery by reducing CST axonal remodeling in the denervated spinal cord and increasing some axonal growth-inhibiting molecules in CNS. Manipulation of astrocytic reactivity post stroke may represent a therapeutic target for neurorestorative strategies.