The Plasminogen Activation System in the Central Nervous System: Implications for Epilepsy and Neuropsychiatric Disorders

Epilepsy is one of the most prevalent neurological disorders, severely impacting quality of life. The burden of epilepsy is exacerbated by high rates of neuropsychiatric comorbidities such as depression, anxiety, and post-traumatic stress disorder. The molecular mechanisms linking epilepsy to these comorbidities remain unclear. Epileptogenesis and recurrent seizures implicate multiple processes including changes in the extracellular matrix, structural and functional neuroplasticity, neuroinflammation, and neurodegeneration. The plasminogen activation (PA) system-a complex system of proteins that function as both proteases and signaling molecules-modulates these processes in the central nervous system (CNS) under normal conditions and following potentially epileptogenic insults. Notably, the PA system is also dysregulated in stress-related psychiatric disorders. In this review, we first provide an overview of the role of PA system in the CNS with an emphasis on the mechanisms related to epilepsy. We then explore the hypothesis that the components of the PA system components constitute a shared pathological link implicated in both epileptogenesis and psychiatric disorders. We summarize clinical and preclinical evidence demonstrating that seizures and other brain insults disrupt the PA system, and that similar dysregulation is observed in stress-related psychiatric conditions. We propose that PA system dysregulation is a potential molecular substrate linking epileptogenesis and neuropsychiatric comorbidities, presenting a promising target for future research aimed at understanding the mechanisms underlying the development of behavioral comorbidities in epilepsy.