Effect of repeated seizures on spatial exploration and immediate early gene expression in the hippocampus and dentate gyrus

Immediate early genes (IEGs) are coordinately activated in response to neuronal activity and can cause activation of secondary response genes that modulate synaptic plasticity and mediate long-lasting changes in behaviour. Excessive neuronal stimulation induced by epileptic seizures induce rapid and dramatic changes in IEG expression. Although the impact of acute seizure activity on IEG expression has been well studied, less is known about the long-term effects of chronic seizures on IEG induction during seizure free periods where behavioural and cognitive impairments are frequently observed in people with epilepsy and in animal models of epilepsy. The present study sought out to examine the impact of chronic pentylenetetrazole evoked seizures (PTZ kindling) on spatial exploration induced in IEG expression (c-Fos, ΔFosB, Homer1a, Egr1, Npas4, Nr4a1) in the hippocampus (CA1 and CA3 subfields) and dentate gyrus of rats. Male rats underwent two weeks of PTZ kindling (every 2 days) or received vehicle injections and were placed into a novel open field arena for 30 min either 24 hrs or 4 weeks after the last treatment. Although exploratory activity was similar between PTZ kindled and vehicle controls when examined 24 hrs after the last treatment, we observed a significant reduction in spatial exploration induced expression of c-Fos, Egr1, and ΔFosB in the hippocampus and dentate gyrus, and reduced expression of Nr4a1 in the dentate gyrus and Homer1a in the hippocampus only. When testing was conducted after a 4-week recovery period, only c-Fos continued to show reduced expression after exposure a novel environment in previously PTZ kindled animals. Interestingly, these animals also showed reduced activity in the center region of the open field suggestive of heightened anxiety-like behaviour. Collectively, these results suggest that repeated seizures may lead to longterm downregulation in hippocampal IEG expression that can extend into seizure free periods thereby providing a critical mechanism for the development of cognitive and behavioural deficits that arise during chronic epilepsy.