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Commentary Animal models of acquired temporal lobe epilepsy (TLE) have informed hypothesis-driven research on the cellular correlates—and possible mechanisms—of epileptogenesis for decades. In particular, electricallyor chemically-induced status epilepticus (SE) in naïve animals results in modification of brain circuits critically involved in seizure generation and propagation. The article by Artinian et al. builds upon what is known about well-established changes in synaptic connectivity in the dentate gyrus that correlate to epileptogenesis in a rodent model of TLE—the pilocarpine-treated rat (1). They analyzed functional increases in both neuronal synchrony and action potential activity arising from a combination of synaptic reorganization, intrinsic ion currents, and glutamate receptor subtype expression changes as components of the reactive plasticity that occurs in the dentate gyrus subsequent to SE induction and development of TLE. An important feature of the TLE model used in this paper is the stereotyped nature of synaptic reorganization occurring after pilocarpine-induced SE. After a latent period of relative inactivity following SE induction, reactive cellular and synaptic plasticity leads to the eventual remodeling of neural circuitry that acts as a substrate upon which seizures appear more likely to be generated. After SE, regulation and expression of numerous genes are altered, select neurons are typically killed, and axons of principal neurons in key areas sprout to form new synaptic connections—often with cells to which they had sparse or no connection before. These events have been especially well-documented in the rodent dentate gyrus, where myriad studies have shown that, coincident with development of spontaneous seizures, new glutamatergic synapses form between granule cells, increasing their overall excitability. The hypothesis that synaptic reorganization among granule cells contributes to hippocampal excitability in the epileptic state has become a staple of many discussions regarding causes and correlates of TLE development in adults. Glutamate released from sprouted mossy fiber terminals results in enhanced excitatory neurotransmission in the dentate gyrus after synaptic reorganization (2), a result consistent with increased activity of NMDA and non-NMDA receptors, and a phenomenon that has been extensively studied for more than two decades. Thus, synaptic reorganization in the dentate gyrus in this and other TLE models, as well as in TLE patients, has been hypothesized to underlie at least some components of the increased seizure susceptibility associated with development of TLE. Recently, a breakthrough finding was added to the reactive plasticity mix. Whereas descriptions of non-NMDA receptor-mediated synaptic responses have typically lumped AMPA and kainate (KA) receptors together, the relatively recent development of selective pharmacological tools allowed Epsztein et al. (3) to unveil distinct KA and AMPA responses in granule cells from epileptic rats. In naïve animals, glutamate-mediated EPSCs in granule cells are mediated by AMPA receptors, whereas after mossy fiber sprouting and synaptic reorganization in the dentate gyrus has occurred, additional KA receptor-mediated responses are expressed. Differentiated Synaptic Kainate Receptors in Interplay With INaP Shift the Sparse Firing of Dentate Granule Cells to a Sustained Rhythmic Mode in Temporal Lobe Epilepsy.

Reactive Plasticity with a Kainate Receptor Twist: Rhythmic Firing in Granule Cells Breaks down the Gate?