The role of synaptic reorganization in mesial temporal lobe epilepsy

Abstract

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.

Figure 1. Mechanisms of Epileptogenesis

The schematic diagram describes the relationships between pathophysiological phenomena and brain location during epileptogenesis in mesial temporal lobe epilepsy. Partial-onset seizures might initially originate in neocortical areas, but after the establishment of intractability, there is a vicious circle of interrelated pathophysiological phenomena within the hippocampal circuitry that self sustains intractable seizures with propagation to neocortical structures.

Figure 2. Mossy Fiber Sprouting

These are three photomicrographs from histological sections of the dentate gyrus (DG) stained with Timm histochemistry. Dark punctate granules depict the projection pattern of mossy fiber terminals that originate from granule cell axons. (A) The dentate gyrus from a normal rat shows dense staining in the hilus (area within the U-shape of the DG) and in the CA3 region, with an absence of dark punctate granules in the molecular layer of the DG (arrow). (B) The dentate gyrus from a rat that experienced status epilepticus induced with kainic acid demonstrates prominent staining in the molecular layer of the DG. (C) Human dentate gyrus obtained surgically during a standard anterior temporal lobectomy for the treatment of pharmacologically intractable mesial temporal lobe epilepsy. Note that the molecular layer of the DG has prominent staining demonstrating mossy fiber sprouting into that region.

Figure 3. Synaptic reorganization in the CA1 projection to subiculum

There is a prominent reorganization of the lamellar projection of the CA1 axonal pathway to the subiculum in several animal models of mesial temporal lobe epilepsy using retrograde tracers. In control rats, the extent of CA1 retrograde labeling from an injection site is limited to a couple of lamellas above and below of the injection site in subiculum. In contrast, in epileptic rats, the retrograde labeling extends beyond several CA1 lamellas above and below the normal projection. This is direct evidence that axonal terminals from neurons in those layers extend their axons into the area of injection (Figure modified from ref. 18).

Figure 4. Synaptic Reorganization in mossy fiber pathway results in translamellar hyperexcitability in the hippocampal formation

The schematic drawings illustrate the normal hippocampal circuitry, the abnormal circuitry during the latent state, and after spontaneous seizures develop in the kainic acid model of mesial temporal lobe epilepsy. The red neurons and axons are excitatory neurons, while the blue neurons are inhibitory interneurons. A. In the normal dentate gyrus, activation of granule cells in a lamella results in a limited activation of the CA3 pyramidal region shown also in red, and the hilar neurons inhibit dentate granule cells in lamellas above and below the activated lamella. B. During the latent state, inhibitory mechanisms are functionally impaired with slow improvement in the inhibitory tone (perhaps, in part, due to synaptic reorganization of inhibitory pathways). There is a mild degree of disinhibition in lamellas above and below the activate lamella (shown as smaller blue block in those lamellas). Furthermore, mild disinhibition results in a greater degree of activation in the CA3 pyramidal region (shown as a greater number of activated red CA3 lamellas). C. Once spontaneous seizures develop in epileptic models, there is prominent synaptic reorganization of the mossy fiber into the inner molecular layer of the DG, across DG blades, and into the basal dendrites of CA3 pyramidal regions. The resulting increased recurrent excitatory connectivity between principal neurons in the hippocampus and within hippocampal lamellas results in translamellar sprouting.

Figure 5. Synaptic Reorganization in CA1 projection to the subiculum results in translamellar hyperexcitability in the hippocampal formation

The schematic drawings illustrate the normal hippocampal circuitry, the abnormal circuitry during the latent state, and after spontaneous seizures develop in the kainic acid model of mesial temporal lobe epilepsy. The red neurons and axons are excitatory neurons, while the blue neurons are inhibitory interneurons. A. In the normal hippocampus, activation of the CA1 pyramidal neurons in a lamella results in a limited activation of subicular neurons shown also in red, and the CA1 interneurons inhibit CA1 pyramidal neurons from lamellas above and below the activated lamella (shown as a blue block over those lamellas). B. During the latent state, inhibitory mechanisms are functionally impaired with slow improvement in the inhibitory tone (perhaps, in part, due to synaptic reorganization of inhibitory pathways). There is a mild degree of disinhibition in lamellas above and below the activate lamella (shown as smaller blue block in those lamellas). Furthermore, mild disinhibition results in a greater degree of activation in subiculum (shown as a greater number of activated subiculum sections). C. Once spontaneous seizures develop in epileptic models, there is prominent synaptic reorganization of the CA1 pyramidal axons making synaptic contacts with additional CA1 pyramidal neurons and subicular neurons in sections (lamellas) above and below their normal projection pattern. The resulting increased recurrent excitatory connectivity between principal neurons in the hippocampus and within hippocampal lamellas results in translamellar sprouting.