The long-term objective of the project is to understand mechanisms of co-morbidity between epilepsy and depression. The present proposal tests the hypothesis that epilepsy-associated depression may stem from specific dysfunction of central noradrenergic transmission. The study focuses on the ascending noradrenergic pathway and on the plasticity of ?2A adrenoreceptors that regulate norepinephrine (NE) release in this pathway. The study employs an animal model whereby chronic epilepsy and concurrent depression-like impairments develop in Wistar rats following pilocarpine-induced status epilepticus. The first part of the study describes perturbations in central noradrenergic transmission in relation to the severity of depressive behavioral impairments, the latter being measured and classified using the forced swim test. The strength and the integrity of noradrenergic transmission in the locus coeruleus-forebrain (i.e. the hippocampus and the neocortex) noradrenergic projections will be measured by means of the in vivo fast cyclic voltammetry, as well as the tyrosine hydroxylase immunofluorescence. The number and the function of ?2A adrenoreceptors that regulate NE release (i.e. somatodendritic autoreceptors in locus coeruleus and axonal autoreceptors in the forebrain), as well those that regulate serotonin release in the forebrain (i.e. heteroreceptors) will be characterized using autoradiography and electron microscopy. The second part of the study examines whether restoring noradrenergic transmission in the ascending pathway exerts therapeutic effects in animals with epilepsy-associated depression. A selective norepinephrine reuptake inhibitor reboxetine will be delivered over two weeks. A selective ?2A adrenoreceptor blocker RX-821002 will be administered locally into the locus coeruleus, the hippocampus, the neocortex, and in raphe nucleus, in order to target specific population of ?2A adrenoreceptors. The effects of treatments on depressive behavior, norepinephrine and serotonin release in the forebrain, tyrosine hydroxylase expression, as well as the number, function and subcellular localization of ?2A adrenoreceptors will be examined using respective techniques listed above. In the third part of the study possible upstream mechanisms leading to central noradrenergic dysfunction will be examined. The dysregulation of the hypothalamo-pituitary-adrenocortical axis will be studied using radioimmunoassay and correlated with the extent of noradrenergic impairments;further the effects of a glucocorticoid receptor blocker mifepristone delivered locally into the locus coeruleus, on central noradrenergic deficits and depressive behavior will be examined. The proposed studies will contribute to our understanding of mechanisms of the comorbidity between epilepsy and depression, to the development of evidence-based therapies of this condition, and to improving of the quality of life in those epilepsy patients who suffer from concurrent depression.
Depression is frequently observed in, and contributes to the poor quality of life in patients with epilepsy;at the same time, mechanisms that underlie epilepsy-associated depression remain 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 contribute to the development of effective therapies and to improving the quality of life in those epilepsy patients who suffer from concurrent depression.
|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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