Inflammatory Astrocytic TGFβ Signaling Induced by Blood–Brain Barrier Dysfunction Drives Epileptogenesis

Under healthy conditions, the brain is protected by the blood–brain barrier (BBB), a selective barrier function of the central nervous system vasculature restricting the passage of most macromolecules and cells from the blood into the brain. BBB dysfunction (BBBD) occurs in various epileptogenic conditions including stroke, traumatic injury, status epilepticus, and aging. This chapter summarizes recent findings which demonstrate that BBBD is sufficient to induce epileptogenesis, and identifies the epileptogenic cascade triggered by BBBD. This cascade includes (1) cross-BBB influx of albumin from the serum into the brain neuropil, (2) albumin binding to and activating astrocytic transforming growth factor beta (TGFβ) receptor ALK5, (3) mounting of inflammatory signaling and TGFβ1 positive feedback, (4) transcriptional changes in astrocytes that induce astrocytic decoupling and downregulation of K and glutamate buffering capacity, (5) degradation of extracellular matrix, and (6) growth of new excitatory synapses and reorganization of neural networks to favor excitatory activity. These changes epitomize the major hallmarks of epileptogenesis across animal models of acquired epilepsy and in tissue samples from patients, providing a “missing link” for how epileptogenic injuries trigger these pathological changes. Inhibition of TGFβR signaling blocks this cascade of events and prevents epileptogenesis. These findings highlight the potential of BBB-stabilizing treatments as an epilepsy-preventive therapeutic approach, and BBBD quantification as a biomarker for predicting postinjury epilepsy outcomes.