Melanocortin 4 Receptor-Dependent Mechanism of ACTH in Preventing Anxiety-Like Behaviors and Normalizing Astrocyte Proteins After Early Life Seizures.

Abstract

Epilepsy, affecting millions globally, often leads to significant cognitive and psychiatric comorbidities, particularly in children. Anxiety and depression are particularly prevalent, with roughly a quarter of pediatric epilepsy patients having a comorbid diagnosis. Current treatments inadequately address these issues. Adrenocorticotropic hormone (ACTH), a melanocortin peptide, has shown promise in mitigating deficits after early life seizures (ELS), potentially through mechanisms beyond its canonical action on melanocortin 2 receptor (MC2R). This study explores the hypothesis that recurrent ELS is associated with long-term anxiety, and that treatment with ACTH can prevent this anxiety through a mechanism that involves melanocortin 4 receptors (MC4R) in the brain. Our findings reveal that ACTH ameliorates anxiety-like behavior associated with ELS, without altering seizure parameters, in wildtype (WT) but not in MC4R knockout (KO) male and female mice. Our findings also show that knocking-in MC4R in either neurons or astrocytes was able to rescue the anxiety-like behavior after ACTH treatment. Further, our results show that ACTH normalizes important astrocytic proteins like Glial Fibrillary Acidic Protein (GFAP) and Aquaporin-4 (AQP4) after ELS. This suggests that ACTH's beneficial effects on anxiety are mediated through MC4R activation in both neuronal and astrocytic populations. This study underscores the therapeutic potential of targeting MC4R as a treatment, highlighting its role in mitigating anxiety-like behaviors associated with ELS.Significance Statement This study reveals a novel mechanism by which ACTH mitigates anxiety-like behaviors and normalizes key astrocyte markers, including GFAP and AQP4, following early life seizures (ELS) in a melanocortin-4 receptor (MC4R) dependent manner. This challenges the notion that ACTH's primary effects are mediated through the melanocortin 2 receptor in the adrenal cortex. This study further shows that ACTH's effects extend beyond seizure control, targeting psychiatric comorbidities, challenging the prevailing assumption that comorbidities are a result of the seizures. These findings not only expand our understanding of ACTH's beneficial effects through MC4R in both neuronal and astrocyte populations, but also suggest new avenues for treating ELS-related comorbidities.