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Episodic memory was studied in WAG/Rij and Wistar rats aged 2 and 6 months in the novel object recognition test. WAG/Rij rats aged 6 months were given ethosuximide (300 mg/kg, 14 days, i.p.) to counter the symptoms of absence epilepsy and comorbid depression. The novel object recognition test consisted of the following phases: an adaptation phase, a familiarization phase (two identical objects), test phase 1 (a familiar object and an unfamiliar object), and test Phase 2 (a familiar object and an unfamiliar object). Exploratory activity (numbers of rearings and excursions to the center of the field) was recorded during the adaptation phase. Episodic memory was tested at 1 h (test phase 1) and 24 h (test phase 2) after the familiarization phase. Episodic memory was evaluated in terms of the index of recognition of the novel object. The novel object index of recognition was not significantly different in WAG/Rij rats from Wistar rats at age 2 months, but was significantly smaller than in Wistar rats at age 6 months. WAG/Rij rats displayed lower exploratory motivation than Wistar rats only at age 6 months. A positive correlation was seen between the index of recognition of the novel object and measures of exploratory motivation (number of rearings without support and number of excursions to the center of the field). Ethosuximide suppressed spike-wave activity, increased exploratory motivation, and improved episodic memory in WAG/Rij rats. The results provide evidence that impairments to episodic memory in the novel object recognition test in WAG/Rij rats may be due to decreased exploratory motivation as one of the symptoms of depression comorbid with absence epilepsy.

WAG-Rij rats are a model of genetic absence epilepsy, characterized by the presence of peak-wave discharges (PWD) on the EEG. The first PWD in WAG-Rij rats are known to occur at age 2–3 months, the number and duration then increasing. However, the evolution of PWD during the progressive development of absence epilepsy in WAG-Rij rats remains uninvestigated. The aim of the present work was to identify developmental changes in the time-frequency dynamics, frequency spectrum, and morphological features of PWD in WAG-Rij rats. The evolution of PWD was studied in individual rats from age two months to age 12 months. PWD were found to form at age 2–4 months, after which morphological changes in PWD were seen. During the progressive development of absence epilepsy, PWD displayed three stages of “maturation.” It is suggested that the age-related evolution of PWD in rats may reflect progressive electrophysiological changes in the somatosensory cortex – a brain area linked with the generation and generalization of PWD.

In the present study it has been shown for the first time that maternal methyl-enriched diet (choline, betaine, folic acid, vitamin B12, L-methionine, zinc) during perinatal period reduces the expression of genetic absence epilepsy and comorbid depression in adult offspring of WAG/Rij rats. This beneficial effect was more pronounced in males compared with females. It is assumed that epigenetic modifications induced by maternal methyl-enriched diet in the offspring at the early stages of ontogenesis might be a possible mechanism underlying the correction of genetically-based pathologic phenotype in WAG/Rij rats. Results suggest that methyl-enriched diet during perinatal period can be potentially used for mitigation or prevention epileptogenesis and depression-like comorbid disorders in people genetically predisposed to absence epilepsy.

We studied peak-wave activity in WAG/Rij rats at ages of 2 and 6 months. We found age-dependent enhancement of peak-wave discharges. At 2 months, the discharges were rare and weak, whereas 6-month-old rats had robust peak-wave discharges. We measured the concentrations of monoamines and their metabolites in 2- and 6-month-old WAG/Rij and Wistar rats in five brain structures: the prefrontal cortex, nucleus accumbens, hypothalamus, striatum, and hippocampus. In 2-month-old WAG/Rij rats, we found a decrease in the concentration of dopamine (DA) metabolites (HVA) in the prefrontal cortex and striatum compared to Wistar rats. In 6-month-old WAG/Rij rats, we found a considerable decrease in the activity of DA system compared to Wistar rats in all five studied brain structures. Concentrations of both DA and its metabolites decreased. We found impairments of learning and memory of WAG/Rij rats compared to Wistar rats. Impairment of learning and memory were more pronounced in 6-month-old WAG/Rij rats compared to 2-month-old WAG/Rij rats. We believe that the DA system not only responds to emotionally positive states but is also a reward and reinforcement system. An increase in the concentration of DA and its metabolites by madopar prevents disturbances of learning and memory. Our general conclusion is that enhancement of absence epilepsy induces a strong deficit of activity of the mesocorticolimbic and nigrostriatal DA system, which induces depression-like behavior and disturbance of learning and memory in WAG/Rij rats. These are the mechanisms of the development of impairments and the integration of these impairments, as well as the aggravation and widening of pathological states.

It has been shown for the first time that rearing by a foster Wistar mother with high level of maternal care (MC) counteracts the expression of genetic absence epilepsy (AE) and comorbid depression – reduces the number, duration and index of spike-wave discharges (SWDs) and immobility time in the forced swimming test, as well as exerts substantial effects on morphology and time-frequency dynamics of SWDs in WAG/Rij rats. It is supposed that increases in MC early in development might be used to counteract epileptogenesis and comorbid depression in people genetically predisposed to AE.