Abstract WP145: Modulating Astrogliosis to Promote Neuroprotection and Plasticity After Stroke

Abstract

Astrocytes react to central nervous system (CNS) injury, including stroke, with a range of molecular and functional changes known as astrogliosis. Although astrogliosis critically impacts neuroprotection and injury-dependent reorganization of the neural network associated with recovery, current lack of molecular tools to effectively manipulate astrogliosis in vivo greatly limits our understanding of how astrogliosis should be targeted to promote neural repair and recovery. We recently identified leucine zipper kinase (LZK) as a potent activator of astrogliosis (Chen et al, Cell Reports , 2018). Manipulating LZK expression in astrocytes, through the use of astrocyte-specific and inducible LZK-knockout or LZK-overexpression mice, enables specificity and versatility in reducing or enhancing astrogliosis respectively. We applied these novel genetic tools to the photothrombotic model of ischemic stroke targeted to the motor cortex in order to determine how best to modulate astrogliosis to promote neuroprotection and axonal plasticity after stroke. Our data show that CNS-systemic stimulation of astrogliosis enhanced neuroprotection, as demonstrated by a 50% reduction in infarct volume and degeneration of corticospinal axons. Furthermore, stimulating astrogliosis promoted stroke-induced axonal plasticity, as demonstrated by more than twofold increase in midline-crossing corticospinal axons originating from the uninjured hemisphere. Our findings suggest a beneficial role of LZK-regulated astrogliosis in post-stroke neuroprotection and plasticity, whose underlying molecular mechanism and therapeutic application are currently being investigated.