In refractory temporal lobe epilepsy, the hippocampal formation seems pivotal in the development of epileptogenesis. Hippocampal neurons are highly vulnerable to excitotoxicity and hypoxia, and the hippocampus often becomes the source of refractory seizures. Recurrent hippocampal seizures also lead to neuronal loss. As neurons die, there is a deafferentation of their synaptic targets, which in turn appears to trigger a structural reorganization that results in re-enervation of those postsynaptic neurons. Although the initial ‘rationale’ for the rewiring of this circuitry might be viewed as homeostatic, morphological plasticity seems to permanently increase the excitatory nature of the hippocampal circuitry, especially after several repeated seizures. These alterations increase susceptibility to later recurrent seizures – i.e., mechanisms contributing to epileptogenesis.

Purpose: The immature rat brain is highly susceptible to seizures, but has a resistance to pathological changes induced by seizures as compared to adult rats. However, prolonged seizures during early-life enhance cellular injury and hyperexcitabitity induced by convulsive insults later in adulthood. The mechanisms underlying these phenomena are not understood. In adult models, the CA1 axons reorganize their projections to subiculum. Seizure induced plasticity in this pathway has not been investigated in immature seizure models, and may contribute to the vulnerability to later seizures.Methods: On postnatal day 15, rats experienced convulsive status epilepticus with kainic acid (KA). Seizure induced plasticity was examined with Timm histochemistry and iontophoretic injections of sodium selenite, a retrograde tracer. Cellular injury was evaluated with Fluoro-Jade B histochemistry.Results: Retrograde tracing experiments determined a 67% larger dorsoventral extent of retrograde labeling in the CA1 pyramidal region after tracer injections in subiculum. The synaptic reorganization of the CA1 projection to subiculum was noted in the absence of overt neuronal injury in subiculum or CA1. In contrast, mossy fiber sprouting was detected into the stratum oriens of CA3 with limited neuronal injury to CA3 pyramidal neurons. No mossy fiber sprouting into the inner molecular layer of the dentate gyrus, or CA1 sprouting into the stratum moleculare of CA1 were noted.Conclusions: The results indicate that the developing brain has distinct mechanisms of seizure induced reorganization as compared to the adult brain. Our experiments show that the concept of "resistance of the immature brain to excitotoxicity" is considerably more complicated than generally believed. Morphological plasticity in the immature brain appears more extensive in distal, but not proximal, projections of hippocampal pathways, and across hippocampal lamellae. The abnormal connectivity between hippocampal lamellae might play a role in the increased susceptibility to injury and hyperexcitability associated with later convulsive insults. (c) 2006 Elsevier B.V. All rights reserved.

The mechanisms underlying mesial temporal lobe epilepsy (MTLE) remain uncertain. Putative mechanisms should account for several features characteristic of the clinical presentation and the neurophysiological and neuropathological abnormalities observed in patients with intractable MTLE. Synaptic reorganization of the mossy fiber pathway has received considerable attention over the past two decades as a potential mechanism that increases the excitability of the hippocampal network through the formation of new recurrent excitatory collaterals. Morphological plasticity beyond the mossy fiber pathway has not been as thoroughly investigated. Recently, plasticity of the CA1 pyramidal axons has been demonstrated in acute and chronic experimental models of MTLE. As the hippocampal formation is topographically organized in stacks of slices (lamellae), synaptic reorganization of CA1 axons projecting to subiculum appears to increase the connectivity between lamellae, providing a mechanism for translamellar synchronization of cellular hyperexcitability, leading to pharmacologically intractable seizures.