(647) Semaphorin 3F Deletion in GABAergic Neurons of a Genetic Model of Autism and Epilepsy induces Neuroinflammation and Endothelial Injury with Disruption of the Blood Brain Barrier

This abstract has been invited to present during the Investigators Workshop Platform poster session

Rationale: Semaphorin is a well-known neurovascular molecule which impacts both neurogenesis and vasculogenesis. Both cell and neurite motility of the neurons and endothelial cells are regulated by semaphorin 3F-Neuropilin 2 (Sema 3F-NRP2) signaling. The immune system and glia also express neuropilins and semaphorins but their function in these cell types is much less clear. Recent evidence suggests that neuropilin two signaling regulates inflammation. Autism spectrum disorder (ASD) and epilepsy are disorders with some evidence for neuroinflammation but little is known about vascular involvement and blood brain barrier function. We aimed to determine whether neuroinflammation we previously described in knockouts for Sema 3F-NRP2 signaling, a murine model of autism and epilepsy, also involved platelet-endothelial activation and injury.

Methods: Using a genetic model of ASD and epilepsy, Semaphorin 3F knockout mice (CRE+FF) and control mice (Cre−FF, Cre+WT, Cre−WT) expressing Semaphorin 3F, we examined physical (brain weight) and electrophysiological (EEG) changes in brain and the expression and distribution of markers of inflammation (iba1 and iNOS) and of oxidative stress (3-nitrotyrosine) in the hippocampus, cortex and amygdala brain regions. In addition, we stained for platelets (CD61) and platelet activation (p-selectin and serotonin) markers and for albumin leakage as an indicator of blood brain barrier integrity.

Results: Sema 3F deletion in interneurons results in brain weight loss and EEG changes and induces signs of neuroinflammation including activation of microglia, iNOS induction, and increased 3-nitrotyrosine. Signs of platelet deposition, activation, and release of serotonin occur in multiple brain regions important in ASD. Finally, along with platelet products, albumin leakage and uptake and outlining of neurons in these regions suggest possible deficits in the blood brain barrier mediated by inflammation.

Conclusions: In summary, disruption of neurovascular molecules signaling molecules, such as Sema 3F-NRP2, may mediate causative pathophysiology in some subgroups with ASD and epilepsy via neuroinflammation, oxidative stress, and compromised BBB integrity.

Funding: Please list any funding that was received in support of this abstract.: American Epilepsy Society