The objective of the project is to validate an experimental model of co-morbidity between depression and temporal lobe epilepsy (TLE), and to establish the mechanistic connection between the two states. Depression has been identified as the most frequent psychiatric co-morbidity in patients with epilepsy, particularly among pediatric population. While depression has been well described in animal models of absence and idiopathic generalized epilepsies, experimental models of TLE-associated depression are scarce. Likewise, no experimental data are available on the correlation between TLE and depression. Such a void in experimental research is a handicap to both studying the mechanisms and to developing rational therapy of depression-TLE co-morbidity. The study will test the hypothesis that in epilepsy patients depression does not necessarily depend on the presence of epileptic seizures or the extent of neurodegeneration, but rather on the chronic increase in network excitability and predisposition to seizures. To induce TLE, two weeks-old Wistar rats will be subjected to LiCl and pilocarpine status epilepticus (SE). Chronic epileptic state will be characterized by quantifying spontaneous seizures by their incidence, frequency and severity, as well as by examining chronically increased excitability through studying interictal spike occurrence, and properties of afterdischarge evoked in the hippocampus. Depression will be characterized by using behavioral tests (forced swim test to examine an ability to adapt active strategies in inescapable stressful situation;saccharin intake to examine an ability to experience pleasure;food intake to examine appetite), biochemical assays of serotonergic transmission (HPLC to detect serotonin concentration in hippocampal tissue and fast cyclic voltammetry to study the strength of raphe-hippocampal serotonergic innervation), and quantitative autoradiography of 5-HT1A serotonin receptors and serotonin transporter in the hippocampus. The studies will be performed repeatedly at different time points, between 3 weeks and 1 year after SE. The parameters of epileptic state and depression will statistically correlated, in order to identify which hallmarks of epilepsy are instrumental for the development of depression The obtained data will contribute to both improved understanding of the mechanisms and to the development of novel effective therapies of such co-morbidity.

Public Health Relevance

Depression is frequently observed in, and contributes to a lowered quality of life in patients with epilepsy. The mechanisms that underlie epilepsy - associated depression are poorly understood, and effective therapies of this condition are lacking. The proposed study is purposed to develop and to characterize a model of epilepsy - associated depression in experimental animals;the existence of such a model will help to both understand the mechanisms and to develop treatments of depression in epilepsy patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH079933-02
Application #
7808046
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Meinecke, Douglas L
Project Start
2009-04-20
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2010
Total Cost
$195,500
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Vezzani, Annamaria; Aronica, Eleonora; Mazarati, Andrey et al. (2013) Epilepsy and brain inflammation. Exp Neurol 244:11-21
Hauptman, Jason S; Dadour, Andrew; Oh, Taemin et al. (2013) Sociodemographic changes over 25 years of pediatric epilepsy surgery at UCLA. J Neurosurg Pediatr 11:250-5
Pineda, Eduardo A; Hensler, Julie G; Sankar, Raman et al. (2012) Interleukin-1? causes fluoxetine resistance in an animal model of epilepsy-associated depression. Neurotherapeutics 9:477-85
Mazarati, Andréy; Maroso, Mattia; Iori, Valentina et al. (2011) High-mobility group box-1 impairs memory in mice through both toll-like receptor 4 and Receptor for Advanced Glycation End Products. Exp Neurol 232:143-8
Pineda, Eduardo A; Hensler, Julie G; Sankar, Raman et al. (2011) Plasticity of presynaptic and postsynaptic serotonin 1A receptors in an animal model of epilepsy-associated depression. Neuropsychopharmacology 36:1305-16
Auvin, Stéphane; Mazarati, Andrey; Shin, Don et al. (2010) Inflammation enhances epileptogenesis in the developing rat brain. Neurobiol Dis 40:303-10
Sankar, Raman; Mazarati, Andrey (2010) Neurobiology of Depression as a Comorbidity of Epilepsy. Epilepsia 51:81
Auvin, Stephane; Shin, Don; Mazarati, Andrey et al. (2010) Inflammation induced by LPS enhances epileptogenesis in immature rat and may be partially reversed by IL1RA. Epilepsia 51 Suppl 3:34-8
Pineda, Eduardo; Shin, Don; Sankar, Raman et al. (2010) Comorbidity between epilepsy and depression: experimental evidence for the involvement of serotonergic, glucocorticoid, and neuroinflammatory mechanisms. Epilepsia 51 Suppl 3:110-4

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