Abstracts

Rationale: Epilepsy that occurs early in life is associated with higher likelihood of developing temporal lobe epilepsy and comorbid disorders such as obsessive-compulsive disorder (OCD). Fronto-striatal circuit dysfunction is implicated in several neuropsychiatric disorders that feature repetitive behaviors, including OCD. Our lab has shown that a rat model of early life seizures (ELS) exhibits frontal lobe dysfunction, which could correlate with a higher likelihood of developing compulsive behaviors. It remains unclear whether consistent pathological features underlying fronto-striatal circuit dysfunction occur following ELS. Using the flurothyl model of ELS we hypothesized that we could produce compulsive behavior via structural impairment of the fronto-striatal circuit. Studies have shown that cannabidiol (CBD), a non-psychotomimetic component of Cannabis, can reduce anxiety. Whether CBD can be used to treat OCD is less clear. In the marble burying task (MBT), used to measure compulsive behaviors in rodents, CBD reduced compulsive “burying” activity in mice. Here, we study the effect of CBD on alterations to fronto-striatal signaling and compulsive behaviors following ELS.

Methods: Seizures were induced in Sprague Dawley rats via flurothyl inhalation five times/day for 10 days from postnatal day (P)15-P25. Immediately following ELS, half of control (CTL) and ELS rats were given 200mg/kg of CBD or vehicle delivered via their drinking water for 10 days. Rodents were implanted with two tetrodes each in the lateral orbitofrontal cortex (LOFC) and the dorsomedial striatum (DMS). The MBT was used to measure compulsive behaviors. This behavior was then compared with the open field task (OFT), used as a measure of anxiety. EEG and video recordings were taken during all behavioral tasks. EEG recordings were analyzed to identify changes to spectral properties (power, frequency) and functional connectivity (phase coherence) in the delta (1-4 Hz), theta (5-12 Hz), and slow gamma (30-50 Hz) bandwidths.

Results: There were no significant differences in behavior in the CBD-treated or untreated rats during MBT or OFT. Referenced to the LOFC, there was a significant decrease in phase coherence in the DMS during the MBT in ELS compared to CTL, but not during OFT. Phase coherence between LOFC and DMS was decreased by post-ELS CBD administration in both CTL and ELS groups, particularly in the theta bandwidth.

Conclusions: ELS leads to task-dependent signaling changes between the LOFC and DMS in adult rats. Phase coherence decreased during the MBT in untreated ELS compared with untreated CTL rats. Following post-ELS CBD treatment, both CTL and ELS rats had reduced phase coherence during the MBT compared with untreated CTL. Despite this, neither the CBD-treated or untreated CTL or ELS group displayed enhanced burying behaviors. This study demonstrates that both ELS and CBD alter functional connectivity between the LOFC and DMS without altering behavior. Whether these functional changes in coherence are beneficial or harmful remains unclear and requires further study.

Funding: This work was supported by Jazz Pharmaceuticals to GLH and NIH Grant NS108765 to GLH.