The neuroprotective role of proliferative reactive astrocytes in the hippocampus, synapse preservation and regeneration following traumatic brain injury

Abstract Astrocytes react to brain injury with progressive changes in gene expression, morphological hypertrophy, and proliferation referred as astrogliosis. The beneficial or detrimental effects of proliferative reactive astrocytes are constantly under debate, and the underlying molecular mechanisms are poorly understood. Our long-term

goal is to dissect the mechanisms underlying the proliferation of reactive astrocytes and its biological function in the hippocampus after traumatic brain injury (TBI), and in order to find the vital targets for TBI treatment. The objective of this grant is to determine the role of platelet-derived growth factor receptor alpha (PDGFR) signaling

in regulating reactive astrocyte proliferation and the neuroprotective effects of proliferative reactive astrocytes in hippocampus-associated functional outcomes post-trauma. The central hypothesis is proliferative reactive astrocytes regulated by PDGFR mediated signaling pathway are neuroprotective by favoring synapse

preservation and regeneration following TBI. The rationale underlying this proposal is that completion mechanism study will provide an ideal tool to study the function of proliferative reactive astrocyte in the hippocampus and which in turn to identify vital targets for therapeutic intervention aiming at functional

improvement after TBI. The central hypothesis will be addressed with pursuing three specific aims. 1) Determine the role of proliferative reactive astrocytes on synaptic alteration and functional outcomes following TBI; and study PDGFR-mediated signaling pathway in reactive astrocyte proliferation; 2) Determine how proliferative

reactive astrocyte play its neuroprotective role in synapse preservation and regeneration following TBI; 3) Determine the neuroprotective effects of astrocytic BDNF overexpression and long-term treatment with BDNF agonist, a small molecule 7,8-Dihydroxyflavone (DHF) on synapse preservation/regeneration and function

improvement after TBI. The proposed research is innovative because we reveal for the first time the role of PDGFRin regulating reactive astrocyte proliferation post-trauma using state-of-art inducible conditional knockout/knockin technique and discover the neuroprotective aspects of proliferative reactive astrocytes in

injured hippocampus. The results will have an important positive impact because they will augment our knowledge on the pathophysiology of TBI, and may offer a novel intervention for better TBI treatment by selectively manipulating reactive astrocytes at the proliferation stage with neuroprotective effects that counteract

synapse loss and facilitate synaptogenesis post-trauma.