{"paper_id":"1eee50cd-603a-42e3-be24-46b3d23ffeab","body_text":"Abstract\nThe risk of developing psychiatric disorders, particularly stress-related disorders such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), is increased threefold in patients with epilepsy. While this increased risk may arise as a consequence of living with epilepsy, shared neurobiological mechanisms, particularly dysregulation of GABAergic signaling, may also contribute. To investigate this link, we investigated the function of GABAergic neurons co-expressing the neuropeptide cortistatin (CST), which has anticonvulsant effects and is implicated in both MDD and PTSD. Targeting CST+ neurons in the prelimbic cortex (PrL), a rodent brain region that is functionally and anatomically similar to the human dorsal anterior cingulate cortex (dACC), we found that ablating CST+ neurons disrupts context-dependent fear renewal, causes spontaneous convulsive seizures, dramatically increases susceptibility to chemically-induced seizures, and increases anxiety-like phenotypes following stressors. We further show that repeated chemogenetic inhibition of CST+ neurons increases the rate of seizure kindling in female mice, and that disruption of brain derived neurotrophic factor signaling in CST+ neurons phenocopies the effects of acute inhibition. These data support the hypothesis that epilepsy and stress-related psychiatric disorders potentially share common neurobiological mechanisms, and that loss of CST+ neuron function may be a critical feature underlying fear dysregulation and cortical hyperexcitability.\nHighlights\nLoss of prelimbic CST+ neurons disrupts fear renewal, causes anxiety-like symptoms, and induces spontaneous seizures.\nInhibition of prelimbic CST+ by chemogenetics or BDNF inhibition by TrkB increases seizure susceptibility in females only.\nCST+ neurons represent a subset of primarily SST and PVALB expressing GABAergic neurons.\nCompeting Interest Statement\nThe authors have declared no competing interest.","source_license":"CC-BY-4.0","license_restricted":false}