UC Berkeley

Traumatic brain injuries (TBIs) cause the breakdown of the blood-brain barrier (BBB) and the extravasation of serum albumin, and induce epileptiform activity via astrocytic transforming growth factor β (TGF-β) signaling. Intracerebroventricular (ICV) infusion of serum albumin alone is sufficient to induce seizures in rodents and has been associated with increased TGF-β signaling and synaptogenesis, which contribute to epileptogenesis. This study demonstrates that ICV infusion of serum albumin also promotes the proliferation of neural stem cells (NSCs) and aberrant neurogenesis in the dentate gyrus of the adult mouse. Treatment with an angiotensin II type 1 receptor antagonist (Losartan) prevents these changes. Furthermore, we demonstrate that serum albumin alone does not affect the proliferation of these NSCs in vitro, and is not sufficient to induce the secretion of astrocytic proliferative signals. This suggests that the increase in proliferation observed in animals exposed to serum albumin may require activity-induced proliferative signals from epileptiform activity, contributions from other cells in the niche in addition to astrocytes, cell-to-cell contact signals, or all three. These observations suggest a mechanism for the increase in neurogenesis observed in the post-injury epileptic brain and offer an opportunity to develop a therapeutic intervention to prevent epileptogenesis after TBIs.