Chronic fluoxetine treatment accelerates kindling epileptogenesis in mice independently of 5-HT2A receptors.

Patients with epilepsy often have mood disorders, and these are commonly treated with antidepressant drugs. Although these drugs are often successful in mitigating depressive symptoms, how they affect the epileptogenic processes has been little studied. Recent evidence has demonstrated that treatment with selective serotonin reuptake inhibitor (SSRI) antidepressant drugs adversely promotes epileptogenesis, which may be of great concern considering the number of patients exposed to these drugs. This study investigated 5-HT2A receptor signaling as a potential mechanism driving the pro-epileptogenic effects of the prototypical SSRI fluoxetine. Male homozygous 5-HT2A receptor knockout mice or wild-type littermates (n = 9-14/group) were treated with continuous fluoxetine (10 mg kg-1 d-1 , sc) or vehicle and subjected to electrical kindling of the amygdala. Compared to vehicle, fluoxetine treatment accelerated kindling epileptogenesis (P < .001), but there was no effect of genotype (P = .75), or any treatment x genotype interaction observed (P = .90). Of interest, fluoxetine treatment increased afterdischarge thresholds in both genotypes (P = .007). We conclude that treatment with fluoxetine promotes epileptogenesis in mice, but this effect is not mediated by 5-HT2A receptors. This suggests that antidepressants may accelerate the onset of acquired epilepsy in patients who have experienced epileptogenic cerebral insults.

DNA methylation mediates persistent epileptiform activity in vitro and in vivo.

Epilepsy is a chronic brain disorder involving recurring seizures often precipitated by an earlier neuronal insult. The mechanisms that link the transient neuronal insult to the lasting state of epilepsy are unknown. Here we tested the possible role of DNA methylation in mediating long-term induction of epileptiform activity by transient kainic acid exposure using in vitro and in vivo rodent models. We analyzed changes in the gria2 gene, which encodes for the GluA2 subunit of the ionotropic glutamate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor and is well documented to play a role in epilepsy. We show that kainic acid exposure for two hours to mouse hippocampal slices triggers methylation of a 5' regulatory region of the gria2 gene. Increase in methylation persists one week after removal of the drug, with concurrent suppression of gria2 mRNA expression levels. The degree of kainic acid-induced hypermethylation of gria2 5' region varies between individual slices and correlates with the changes in excitability induced by kainic acid. In a rat in vivo model of post kainic acid-induced epilepsy, we show similar hypermethylation of the 5' region of gria2. Inter-individual variations in gria2 methylation, correlate with the frequency and intensity of seizures among epileptic rats. Luciferase reporter assays support a regulatory role for methylation of gria2 5' region. Inhibition of DNA methylation by RG108 blocked kainic acid-induced hypermethylation of gria2 5' region in hippocampal slice cultures and bursting activity. Our results suggest that DNA methylation of such genes as gria2 mediates persistent epileptiform activity and inter-individual differences in the epileptic response to neuronal insult and that pharmacological agents that block DNA methylation inhibit epileptiform activity raising the prospect of DNA methylation inhibitors in epilepsy therapeutics.