Position- and Time-Dependent Arc Expression Links Neuronal Activity to Synaptic Plasticity During Epileptogenesis

Philipp Janz, Pascal Hauser, Katharina Heining, Sigrun Nestel, Matthias Kirsch, Ulrich Egert, Carola A. Haas

In mesial temporal lobe epilepsy (mTLE) an initial precipitating injury can trigger aberrant wiring of neuronal circuits causing seizure activity. While circuit reorganization is known to be largely activity-dependent, the interactions between neuronal activity and synaptic plasticity during the development of mTLE remain poorly understood. Therefore, the present study aimed at delineating the spatiotemporal relationship between epileptic activity, activity-dependent gene expression and synaptic plasticity during kainic acid-induced epileptogenesis in mice. We show that during epileptogenesis the sclerotic hippocampus differed from non-sclerotic regions by displaying a consistently lower power of paroxysmal discharges. However, the power of these discharges steadily increased during epileptogenesis. This increase was paralleled by the upregulation of the activity-related cytoskeleton protein (Arc) gene expression in dentate granule cells (DGCs) of the sclerotic hippocampus. Importantly, we found that Arc mRNA-upregulating DGCs exhibited increased spine densities and spine sizes, but at the same time decreased AMPA-type glutamate receptor (AMPAR) densities. Finally, we show that in vivo optogenetic stimulation of DGC synapses evoked robust seizure activity in epileptic mice, but failed to induce dendritic translocation of Arc mRNA as under healthy conditions, supporting the theory of a breakdown of the dentate gate in mTLE. We conclude that during epileptogenesis epileptic activity emerges early and persists in the whole hippocampus, however, only the sclerotic part shows modulation of discharge amplitudes accompanied by plasticity of DGCs. In this context, we identified Arc as a putative mediator between seizure activity and synaptic plasticity.