Effect of long-term spontaneous recurrent seizures or reinduction of status epilepticus on the development of supragranular mossy fiber sprouting
Introduction
A proposed classification of temporal lobe epilepsy based on tissue analysis has indicated three major groups: medial temporal lobe epilepsy (MTLE), mass associated medial temporal lobe epilepsy (MaMTLE) and paradoxical medial temporal lobe epilepsy (PaTLE) (Spencer and Spencer, 1994). In patients with MTLE retrospective analysis of clinical histories often indicate that a previous cerebral injury has taken place prior to the onset of their habitual complex partial seizures (Falconer et al., 1964) in addition to major neuronal loss and synaptic reorganization (Babb et al., 1984, Babb et al., 1991). Both the kainate (in its various versions) and the pilocarpine models have been shown to mimic many features of MTLE (Cavalheiro et al., 1982, Tauck and Nadler, 1985, Cavalheiro et al., 1991, Mathern et al., 1995, Mathern et al., 1997, Wuarin and Dudek, 1996) MaMTLE, is most often associated with a glioma and is associated with much more subtle neuronal loss and synaptic reorganization (Mathern et al., 1995, Mathern et al., 1997). We have recently suggested that induction of status epilepticus with pilocarpine (or intrahippocampal kainate) in the presence of a protein synthesis inhibitor (cycloheximide) might mimic certain features of MaMTLE (Longo and Mello, 1998). Finally, PaTLE patients have a variable history and a neuropathological profile similar to MaMTLE (Spencer and Spencer, 1994). So far no model has been proposed to specifically study this later condition.
A long-standing debate in TLE is centered on the relationship between seizures and neuropathology. Do repeated seizures cause neuronal loss? Do repeated seizures cause synaptic reorganization? Or rather than cause, are they both the consequences of seizures? Or are they both cause and consequence? The answers to these questions might be different for each of the different above mentioned conditions MTLE, MaMTLE and PaTLE.
From its original description in the kainate model by Tauck and Nadler (1985), supragranular mossy fiber sprouting (MFS) rose to become the leading theory to explain, at least in part, the hyperexcitability of epileptic tissue. The description of intense MFS in human material was fundamental in this process (Sutula et al., 1989, Babb et al., 1991). In 1988, it was shown that kindling also could induced MFS (Sutula et al., 1988). Similarly to all kindled rats, many patients with MFS do not have a history of preceding status epilepticus (SE). Whereas in human cases there is rarely (if ever) 100% confidence on the patients clinical history this is not the case with rats. Therefore, such data supported the notion that SE was not necessary for MFS to develop. As for neuronal loss in kindling the data tends to support the notion that neuronal degeneration might follow kindled seizures (Cavazos and Sutula, 1990) despite evidence on the contrary (Bertram et al., 1990).
Data from SE models (mostly kainate and pilocarpine) tend to support the notion that SE itself is a crucial event for the onset of neuronal loss, MFS and spontaneous seizures (Ben-Ari, 1985, Tauck and Nadler, 1985, Cronin and Dudek, 1988, Cavalheiro et al., 1991, Mello et al., 1993, Lemos and Cavalheiro, 1995). The influence of single spontaneous seizures on neuronal damage in the pilocarpine model has been shown to concentrate on specific cell populations and not to contribute significantly to the overall cell loss (Covolan and Mello, 1996). The influence of single spontaneous seizures on MFS, however, has been a more elusive subject. Here we used the induction of SE with pilocarpine in the presence of cycloheximide, a condition that blocks SE-induced MFS but does not affect epileptogenesis and the onset of spontaneous seizures (Longo and Mello, 1997) to address this and other issues.
Section snippets
Methods
Adult male Wistar EPM-1 rats (200–250 g) were kept on a standard light/dark cycle (12/12 h) and fed ad libitum. The protocols were approved by the Animal Care and Use Ethic Committee at the University.
Results
For the two experiments a total of 85 animals were injected with Pilo (n=32) or CHX+Pilo (n=53). Twenty eight animals (33% of the total) did not develop SE, 20 (37%) were CHX+Pilo and 8 (25%) were Pilo (χ2 P=0.23). Of these, five animals (one Pilo-injected and four CHX+Pilo-injected) were kept together with the experimental groups and sacrificed after 9 months of the attempted (unsuccessful) SE induction. Of the 33 animals injected with CHX+Pilo that developed SE, 16 (48%) died prior to
Discussion
Our findings indicate that, whatever the mechanisms through which CHX is able to block Pilo-induced supragranular MFS, this synaptic reorganization can still be induced in these same animals after either a long time interval or SE-reinduction. As previously shown (Longo and Mello, 1997, Longo and Mello, 1998), a single SE event triggered by Pilo or intrahippocampal kainate in the presence of CHX is not able to induce supragranular MFS (as assessed 60 days after SE induction). Animals undergoing
Acknowledgements
We thank Ivone de Paulo for technical assistance. This work was supported by: FAPESP, CNPq and PRONEX; B. Longo is a PhD fellow of FAPESP (96/6623-2).
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2013, Neuroscience and Biobehavioral ReviewsCitation Excerpt :This is followed by the occurrence of seizures that start in the hippocampus (Bragin et al., 2009; Carriero et al., 2012; Mathern et al., 1993) (Fig. 1). These seizures may then propagate to the ipsilateral amygdala (Akaike et al., 2001), and eventually to the contralateral amygdala, hippocampus and frontal cortex (Leite et al., 1996; Longo and Mello, 1999; Riban et al., 2002; Tanaka et al., 1982). A similar pattern of propagation occurs following intra-amygdaloid injections of KA.
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2011, NeuropharmacologyCitation Excerpt :Therefore the decrease in mossy fiber sprouting occurring in CRS90ALE rats compared to DZP or CRS90TLE rats might contribute to the delay or suppression of motor SRS by decreasing the level of hippocampal hyperexcitability. However, no straightforward relationship between sprouting and frequency of SRS was observed (Longo and Mello, 1999; Nissinen et al., 2001), suggesting that other epileptogenic changes contribute to the development of the hyperexcitable circuit leading to SRS. Altogether, the present data are in favour of a link between sprouting and SRS occurrence and possibly also with the genesis of the epileptic circuit
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2011, Epilepsy and BehaviorCitation Excerpt :In contrast, MFS could also represent a compensatory or inhibitory response [16,17]. A great deal of controversy surrounds the interpretation of the functional role of this sprouting [18–23]. Thus, in the context of the aforementioned studies, determining the morphological alterations at the synaptic and molecular levels that occur in epileptic animals is still challenging.
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2009, Encyclopedia of Basic Epilepsy ResearchThe adenosine kinase hypothesis of epileptogenesis
2008, Progress in NeurobiologyUnmasking recurrent excitation generated by mossy fiber sprouting in the epileptic dentate gyrus: an emergent property of a complex system
2007, Progress in Brain ResearchCitation Excerpt :At the circuit level, numerous past studies of specific molecular or cellular alterations associated with epilepsy have been pursued as possible mechanistic “causes” of the disorder, and then dismissed when it is recognized that sporadically expressed emergent phenomena, such as network synchronization or behavioral seizures, are not universally or linearly related to the specific defect (Dudek, 2002). This interpretive flaw is common in epilepsy research, and has been contributed to skepticism about the function and importance of mossy fiber sprouting (Armitage et al., 1998; Longo and Mello, 1998, 1999; Timofeeva and Peterson, 1999; Mohapel et al., 2000; Nissinen et al., 2001; Romcy-Pereira and Garcia-Cairasco, 2003; Sloviter et al., 2006). Experiments seeking to define the functional effects of mossy sprouting in the complex system of the reorganized dentate gyrus must include design and interpretive perspectives recognizing that sprouting is but one alteration among the many molecular and cellular alterations in epileptic neural circuitry.