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

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 the melanocortin 2 receptor. 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 the melanocortin 4 receptor (MC4R) in the brain. Our findings reveal that ACTH ameliorates anxiety-like behavior associated with ELS, without altering seizure parameters, in wild-type but not in male and female MC4R knock-out 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. Furthermore, our results show that ACTH normalizes important astrocytic proteins like glial fibrillary acidic protein and aquaporin-4 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.