Abstract
The impact of febrile seizure has been shown to transcend immediate generation with the alteration of glutamatergic pathway being implicated. However, transgenerational effects of this neurological disorder particularly prolonged febrile seizure (PFS) on neurobehavioral study and methylation profile is unknown. We therefore hypothesized that transgenerational impact of prolonged febrile seizure is dependent on methylation of hippocampal mGluR1 gene. Prolonged febrile seizure was induced on post-natal day (PND) 14, by injecting lipopolysaccharide (LPS; 217μg/kg ip) and kainic acid (KA; 1.83 mg/kg ip). Sucrose preference test (SPT) and Forced swim test (FST) were carried out in the first generation (F0) of animals at PND37 and PND60. The F0 rats were decapitated at PND 14, 37 and 60 which corresponded to childhood, adolescent and adulthood respectively and their hippocampal tissue collected. The second generation (F1) rats were obtained by mating F0 generation at PND 60 across different groups, F1 rats were subjected to SPT and FST test on PND 37 only. Decapitation of F1rats and collection of hippocampal tissues were done on PND 14 and 37. Assessment of mGluR5 and mGluR3 mRNA was done with PCR while mGluR1 methylation profile was assessed with the Quantitative MassARRAY analysis. Results showed that PFS significantly leads to decreased sucrose consumption in the SPT and increased immobility time in the FST in both generations of rats. It also leads to significant decrease in mGluR5 mRNA expression with a resultant increased expression of mGluR3 mRNA expression and hypermethylation of mGluR1 gene across both generations of rats. This study suggested that PFS led to behavioral changes which could be transmitted on to the next generation in rats.
Highlights
Febrile seizure is the most prevalent seizure type, affecting 3% to 5% of infants between the ages of 3months and 5years [1,2]
We examined the effect of neonatal prolonged febrile seizure (PFS) on Sucrose preference test (SPT) and Forced swim test (FST) in rats from adolescence to adulthood in the F0 generation and at the adolescent age in the F1 generation
We looked at the effects of PFS on hippocampal mGluR1gene, mGlur5 mRNA and mGluR3mRNA at different timelines across both F0 and F1 generations of rats
Summary
Febrile seizure is the most prevalent seizure type, affecting 3% to 5% of infants between the ages of 3months and 5years [1,2]. It is caused by infections (including respiratory tract infection, gastroenteritis and otitis media) that trigger the immune system leading to inflammatory responses with a subsequent release of macrophages, neutrophils and pro-inflammatory cytokines [3,4]. One important factor that lead to the characterized aberrant neuronal excitability in febrile seizure, is neurotransmitter imbalance between glutamate and γ aminobutyric acid (GABA) [8]. The metabotropic glutamate receptor 3 (mGluR3) regulates glutamate release on the presynaptic membrane and glia cell [10]. Likewise hypermethylation of mGluR1 gene has been reported in malignant melanoma in mouse [13] and in the hippocampus of prenatal stressed rats offspring with depression [14,15]
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