MC4Rs Facilitate ACTH-Associated Neuroprotection of Prefrontal Cognition in a Mouse Model of Recurrent Early Life Seizures
Abstract number :
1.04
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2021
Submission ID :
1826534
Source :
www.aesnet.org
Presentation date :
12/4/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:54 AM
Authors :
Colin Villarin, BS - University of Vermont; Jake Spiegler - Neurological Sciences - University of Vermont; Mohamed Khalife - Neurological Sciences - University of Vermont; Emily Tardie - Neurological Sciences - University of Vermont; Khalil Abed Rabbo - Neurological Sciences - University of Vermont; Rod Scott - Neurological Sciences - University of Vermont; J. Matthew Mahoney - The Jackson Laboratory; Amanda Hernan - Neurological Sciences - University of Vermont
Rationale: Early Life Seizures (ELS) are often associated with subsequent cognitive deficits that can affect quality of life into adulthood. Clinical observation of children with infantile spasms, a form of epilepsy, has indicated that exogenously administered adrenocorticotropic hormone (ACTH) is effective in treating seizures and may be associated with better cognitive outcome than other AEDs. Our work supports this observation, showing that a rat model of recurrent ELS treated with ACTH has improved cognitive outcomes when compared to a vehicle-treated control. Despite this observation, the pathways connecting ACTH treatment and prevention of cognitive deficits has not yet been clarified. We hypothesized that treatment with ACTH during ELS prevents cognitive deficits in adulthood, and that this neuroprotective effect is mediated by ACTH acting as an agonist of melanocortin 4 receptors (MC4Rs) in the brain.
Methods: Wild type mice were randomized to ACTH or vehicle-treated groups and subjected to an ELS protocol, or handled but not exposed to seizures. All groups were then subsequently tested on a behavioral battery to quantify the effects of seizures and treatment on prefrontal cognition in adulthood. A transgenic MC4R global knockout mouse was also implemented in an attempt to isolate a possible treatment pathway. We further analyzed seizure and behavioral data to identify potential differences between treatment and genotype effects.
Results: Our findings with WT animals confirmed that ELS results in fear extinction learning deficits in adulthood (p< 0.001, main effect of group), with no group differences found in the acquisition of the fear learning task. These deficits were prevented by ACTH treatment during ELS (p=0.04, main effect of treatment.) Knockout animals also displayed no differences in fear task acquisition between groups, with significant impairment in extinction learning after seizures, while the lack of MC4Rs did prevent ACTH treatment from eliciting its protective effect on cognition. No significant differences were found in seizure characteristics with treatment.
Basic Mechanisms