Abstracts

This is a Late Breaking abstract

Rationale: Neurovascular coupling, the dynamic process whereby local neural activity induces changes in local cerebral blood flow (CBF), and vice versa, is key for maintaining properly oxygenated and functioning brain tissue. Increases in local neural activity recruits greater blood flow to meet the larger metabolic demand. Seizures present a sustained intense and synchronous discharge of neural activity which requires an adequate increase in CBF so that neural function may continue, alluding to the importance of the vasculature in maintaining and perpetuating the seizure. Typical investigation of seizures focuses on the neural component as the driver; however, the question remains what role the vasculature plays in driving seizure development, progression, and termination, and how a disruption of the neurovascular coupling may worsen seizures. Our current work in mice probes neurovascular coupling during seizures and assesses how modification to the contractility of arteries and arterioles in the brain is related to seizure progression.

Methods: Mice were implanted with a miniature microscope (Inscopix nVoke) above the right somatosensory cortex to allow fluorescent imaging of vasculature after retroorbital injection of fluorescein isothiocyanate–dextran (Fitc-dextran) to determine arterial diameters. Simultaneous implantation of an electrode adjacent to the imaging area was used to record neural activity (epileptic spikes) before and after challenging the mice with an intraperitoneal injection of a pro-convulsant pentylenetetrazole (PTZ, 70 mg/kg; n=14 mice). A subset of mice received, in addition to PTZ, an injection of the nitrous oxide synthase antagonist, NG-nitro-L-arginine methyl ester (L-NAME, 200 mg/kg; n=13 mice), to investigate to what extent disrupting neurovascular coupling affects seizures.

Results: Analysis revealed vascular contractions occurring at both the onset and offset of seizures. Preliminary assessment demonstrated a relationship between the seizure duration and the timing of contractions at seizure onset (p < 0.018). In addition, faster contractions at the start of seizures were correlated with shorter seizure durations (p = 0.006). L-NAME treatment led to a loss of any relationship between the seizure onset contraction and seizure duration. L-NAME treated mice also were more likely to have severe seizures in which fast spiking epileptic spikes ( >2 spikes/sec) occurred (p = 0.032).

Conclusions: To our knowledge, this work represents the first investigation of neurovascular coupling in freely behaving seizing mice. We find that the faster arterial contractions that occur closer to the start of the seizure are correlated with shorter seizures. This finding suggests that the arterial contractions at the onset of a seizure may play a protective role. Elucidating the role of the vasculature in neurovascular coupling will lead to the identification of new biomarkers (e.g., vascular contractility) associated with seizure disorders.

Funding: None