Molecular and Behavioral Correlates of Interictal Spiking

Interictal spikes are brief (< 200 ms), paroxysmal, high-amplitude discharges observed on electroencephalogram (EEG) between seizures in patients with epilepsy. The relationship between interictal spikes and seizures remains unclear, but spikes often occur more frequently than seizures and are often observed in the same brain regions that produce seizures. In patients with epilepsy and its associated comorbidities, interictal spikes can have deleterious effects, including effects on cognition and behavior. To that end, spikes are also observed in patients with mental health disorders, including attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). It has been historically challenging to understand the distinct role of interictal spikes; most animal models exhibit both spikes and seizures, making it difficult to study the relationship between spiking and behavior in a seizure-free context. Our lab has developed a rat model of interictal spiking, where rats develop high levels of spiking activity without seizures. This model uses tetanus toxin which, when injected into the somatosensory cortex, yields consistent and reproducible spikes beginning around 14 days post-injection. To understand the molecular underpinnings of interictal spikes, our lab conducted transcriptional profiling studies comparing high- and low-spiking areas as well as seizure onset zones in epileptic human cortex. In high-spiking areas, we found a sustained increase in the mitogen-activated protein kinase (MAPK) pathway. Immunohistochemical studies confirmed that increased MAPK activity is localized to cortical layers I-III in high-spiking brain regions. Using our rat model of neocortical epilepsy, we tested the relationship between MAPK signaling and the development of interictal spikes by inhibiting the MAPK pathway at various times in the epileptogenic process. We’ve shown that both early and delayed MAPK inhibition can effectively reduce interictal spiking. Furthermore, MAPK inhibition alters specific morphological spike properties and preserves cortical cytoarchitecture, resulting in subsequent behavioral alterations.