Abstracts

Rationale: Depression is a common comorbidity in pediatric epilepsy patients. Such biological factors as chronic stress associated with recurrent seizures, hippocampal neurodegeneration, and chronic limbic system dysfunction have been implicated in the mechanisms of depression. Using kindling model of epilepsy, we examined whether depression develops in immature animals during epileptic process in the absence of both spontaneous seizures and explicit morphological hippocampal abnormalities.Methods: The experiments were done in adolescent male Wistar rats, thirty five days or of age at the beginning of the study. Animals underwent rapid kindling - 84 initially subconvulsive electrical stimulations of ventral hippocampus delivered every five minutes. Seizure susceptibility was evaluated by quantifying afterdischarge properties and behavioral seizures in response to threshold stimulation. Behavioral tests of depression included studying an ability to adapt active strategy in inescapable stressful situation (immobility time in forced swim test, FST); an ability to experience pleasure (taste preference in calorie-free saccharin intake test); appetite (consumption of calorie-containing sucrose solution). Biochemical assays included measuring serotonin (5HT) concentration in the hippocampus (high performance liquid chromatography) and 5HT release from the hippocampus in response to raphe stimulation (fast cyclic voltammetry).Results: Rapid kindling led to chronic (>4 weeks) increase of seizure susceptibility, evident as the increase of afterdischarge duration and the development of secondary generalized limbic seizures in response to threshold stimulation. Kindled animals exhibited increased immobility time in FST (60-80% of total test duration as compared to 30-40% in controls); loss of taste preference in saccharin intake test; and the increase of appetite. 5HT concentration in the hippocampus was reduced by 35-40% as compared with controls. 5HT release from the hippocampus was depleted by 70% in CA1 and by 30% in CA3 with no differences between hippocampi ipsilateral and contralateral to kindling stimulation. Positive correlation was observed between the severity of seizures induced by test stimulation and the extent of the symptoms of depression. No neuronal injury was found in the hippocampi of kindled animals.Conclusions: Chronic increase of hippocampal excitability and predisposition to seizures induced by kindling in immature rats was accompanied by such symptoms of depression as despair (FST), anhedonia (loss of taste preference in sucrose test), increased appetite (calorie consumption), as well as by compromised serotonergic transmission in the raphe-hippocampal projection. These changes occurred in the absence of both spontaneous seizures and neurodegeneration. We conclude that chronic limbic system dysfunction and changes in network excitability associated with epilepsy, may translate into the development of interictal dysphoric syndrome. Supported by NIH grants NS043409, NS046516, NS32070, MH067187, and the DAPA Foundation.