The long-term objective of the project is to understand mechanisms of co-morbidity between epilepsy and depression. The current study tests the hypothesis that epilepsy is accompanied by chronic interictal dysregulation of the hypothalamo-pituitary-adrenocortical (HPA) axis, which in turn compromises raphe- hippocampal serotonergic pathway, and via the latter mechanism leads to the development of depression. We will employ a model of chronic epilepsy that develops in male Wistar rats following pilocarpine - induced status epilepticus (SE). The first part of the project is designed to prove that epilepsy is accompanied by the interictal dysregulation of the HPA axis. This will be achieved by measuring, using radioimmunoassay, both basal and dexamethasone/corticotropine releasing hormone (DEX/CRH)- induced increase of plasma corticosterone (CORT) levels during chronic stage of epilepsy (8-12 weeks after SE). Increased CORT level will be statistically correlated with behavioral and electrographic parameters of epilepsy (frequency of spontaneous seizures) and interictal increase of hippocampal excitability determined in the afterdischarge test). The purpose of the second part is to prove that the dysregulation of the HPA axis compromises raphe- hippocampal serotonergic pathway, specifically through the upregulation of raphe 5-HT1A autoreceptors. In post-SE animals, we will correlate the increase in plasma CORT levels with the decrease of raphe- hippocampal serotonergic transmission, as measured by fast cyclic voltammetry (FCV) in vivo, and with the functional state of raphe 5-HT1A autoreceptors, as measured by autoradiography. Further, we will examine, whether epilepsy-associated decrease of serotonin release in the hippocampus and the upregulation or raphe 5-HT1A autoreceptors can be reversed by the protracted pharmacological blockade of glucocorticoid receptors on the level of dorsal raphe. We will also examine whether pharmacological blockade of raphe 5- HT1A autoreceptors restores the functioning of raphe-hippocampal serotonergic pathway. The third part of the project addresses the question whether the dysregulation of the HPA axis and subsequent impairment of raphe-hippocampal serotonergic transmission translates into the development of depression. In post-SE animals, we will statistically correlate plasma CORT levels with the severity of behavioral equivalents of depression - despair, as examined in the forced swim test, and anhedonia, analyzed using saccharin consumption taste preference test. We will also investigate whether protracted blockade of raphe glucocorticoid receptors and of 5-HT1A autoreceptors alleviate depressive behavior in epileptic animals. Data obtained in the proposed studies will likely advance our understanding of the mechanisms, and the development of effective therapies of co-morbidity between epilepsy and depression.

Public Health Relevance

Depression is frequently observed in, and contributes to a lowered quality of life in patients with epilepsy;at the same time, mechanisms that underlie epilepsy-associated depression are poorly understood, and effective therapies of this condition are lacking. The proposed project uses an experimental model of epilepsy to examine a possible mechanism that leads to the development of depression in epilepsy patients. Advancement of knowledge in this area will likely contribute to the development of effective therapy and the improvement of quality of life in those patients who suffer from both epilepsy and depression.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Fureman, Brandy E
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Mazarati, Andrey; Jones, Nigel C; Galanopoulou, Aristea S et al. (2018) A companion to the preclinical common data elements on neurobehavioral comorbidities of epilepsy: a report of the TASK3 behavior working group of the ILAE/AES Joint Translational Task Force. Epilepsia Open 3:24-52
Medel-Matus, Jesús-Servando; Shin, Don; Dorfman, Edward et al. (2018) Facilitation of kindling epileptogenesis by chronic stress may be mediated by intestinal microbiome. Epilepsia Open 3:290-294
Medel-Matus, Jesús-Servando; Reynolds, Ashley; Shin, Don et al. (2017) Regulation of kindling epileptogenesis by hippocampal Toll-like receptors 2. Epilepsia 58:e122-e126
Medel-Matus, Jesus-Servando; Shin, Don; Sankar, Raman et al. (2017) Galanin contributes to monoaminergic dysfunction and to dependent neurobehavioral comorbidities of epilepsy. Exp Neurol 289:64-72
Medel-Matus, Jesús-Servando; Shin, Don; Sankar, Raman et al. (2017) Kindling epileptogenesis and panic-like behavior: Their bidirectional connection and contribution to epilepsy-associated depression. Epilepsy Behav 77:33-38
Medel-Matus, Jesús-Servando; Shin, Don; Sankar, Raman et al. (2017) Inherent vulnerabilities in monoaminergic pathways predict the emergence of depressive impairments in an animal model of chronic epilepsy. Epilepsia 58:e116-e121
Mazarati, Andrey; Sankar, Raman (2016) Common Mechanisms Underlying Epileptogenesis and the Comorbidities of Epilepsy. Cold Spring Harb Perspect Med 6:
Dupuis, Nina; Mazarati, Andrey; Desnous, Béatrice et al. (2016) Pro-epileptogenic effects of viral-like inflammation in both mature and immature brains. J Neuroinflammation 13:307
Kumar, Udaya; Medel-Matus, Jesus-Servando; Redwine, Hannah M et al. (2016) Effects of selective serotonin and norepinephrine reuptake inhibitors on depressive- and impulsive-like behaviors and on monoamine transmission in experimental temporal lobe epilepsy. Epilepsia 57:506-15
Washington 3rd, James; Kumar, Udaya; Medel-Matus, Jesus-Servando et al. (2015) Cytokine-dependent bidirectional connection between impaired social behavior and susceptibility to seizures associated with maternal immune activation in mice. Epilepsy Behav 50:40-5

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