Chronic ΔFosB expression and increased AP-1 transcription factor binding are associated with the long term plasticity changes in epilepsy

Morris, Terry; Jafari, Nesa; DeLorenzo, Robert J.

doi:10.1016/s0169-328x(00)00112-1

Cited by 56 publications

(46 citation statements)

References 39 publications

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“…Furthermore, ⌬FosB expression and AP-1 (activator protein-1) complex DNA binding also were found to be permanently elevated in this model of AE (30). NMDA-receptor activation and subsequent calcium entry stimulates the expression and activity of SRF and ⌬FosB (29,30). Thus, the long-term elevation of [Ca 2ϩ ] i during epileptogenesis and in the chronic-epileptic state may directly or indirectly affect the expression of these, and perhaps other, specific Ca 2ϩ -regulated transcription factors.…”

Section: Discussionmentioning

confidence: 61%

“…In the pilocarpine model of AE, the expression of the Ca 2ϩ -modulated transcription factor, serum response factor (SRF), is permanently elevated, along with its ability to bind to its DNA consensus sequence serum response element (29). Furthermore, ⌬FosB expression and AP-1 (activator protein-1) complex DNA binding also were found to be permanently elevated in this model of AE (30). NMDA-receptor activation and subsequent calcium entry stimulates the expression and activity of SRF and ⌬FosB (29,30).…”

Section: Discussionmentioning

confidence: 84%

See 1 more Smart Citation

Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsy

Raza

Blair

Sombati

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

109

135

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Alterations in hippocampal neuronalneuronal plasticity ͉ pilocarpine model ͉ calcium homeostasis ͉ seizure E pilepsy is one of the most common neurological disorders (1), and Ϸ40% of epilepsies are acquired, meaning that the epileptic condition is acquired through an injury to the nervous system (2, 3). Epileptogenesis is the process by which an injury such as status epilepticus (SE), stroke, or traumatic brain injury produces long-term plasticity changes in neurons, resulting in spontaneous recurrent seizures [acquired epilepsy (AE)] in previously normal brain tissue (4-6). AE develops in three phases: injury (brain insult), epileptogenesis (latency), and, finally, chronic epilepsy (spontaneous recurrent seizure) (7). The molecular basis for developing AE is still not completely understood. However, there is growing evidence from the SE and glutamate injury-induced models of AE that elevated intracellular calcium concentration ([Ca 2ϩ ] i ) and altered Ca 2ϩ -homeostatic mechanisms (Ca 2ϩ dynamics) may play a role in the development of AE (6,(8)(9)(10)(11)(12)(13). In addition, altered Ca 2ϩ dynamics have been observed in the hippocampus of chronic epileptic animals as long as 1 year after the induction of seizures in the in vivo pilocarpine model of AE (14). This model of AE shares many of the clinical and pathophysiological characteristics of partial-complex or temporal-lobe epilepsy in humans (14-19). The hippocampus has been shown to be the focus for many of the plasticity, pathophysiological, and epileptogenic alterations in the pilocarpine model of AE (14-19). Thus, if Ca 2ϩ is involved as a second messenger in the inductions and maintenance of AE in the pilocarpine model, it would be expected that Ca 2ϩ dynamics should be altered immediately after SE and in the three phases of the development of AE.This study was undertaken to determine whether hippocampal neuronal Ca 2ϩ dynamics are altered immediately after SE and in the three phases of the development of AE.Ca 2ϩ dynamics were evaluated in acutely isolated CA1 hippocampal, frontal, and occipital neurons at several time points during the injury, epileptogenesis, and chronic-epilepsy phases of AE. The effects of NMDA receptor inhibition by (ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK801) on both the development of seizures and Ca 2ϩ dynamics were determined. Comparisons of sham (salinetreated), pilocarpine without SE, and pilocarpine with SE but without AE control animals with SE animals with AE indicated that Ca 2ϩ dynamics were significantly altered during the development of AE and that both changes in Ca 2ϩ dynamics and the development of AE could be blocked by inhibition of the NMDA receptor during SE. The results demonstrate that altered Ca 2ϩ dynamics were associated with the development of AE and that inhibition of these changes in Ca 2ϩ dynamics was associated with the inhibition of the development of AE. The results provide direct evidence that Ca 2ϩ dynamics are significantly altered during epileptogenesis and ...

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 84%

Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsy

Raza

Blair

Sombati

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

109

135

View full text Add to dashboard Cite

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“…Here we found that a similar increment also took place in temporal and entorhinal cortices of marmosets as a consequence of the chronic epileptic condition due to pilocarpine, hence generalizing the enhanced FosB expression to other areas of seizure propagation. FosB expression is conditioned to the activation of serum response factor (SRF) in response to repetitive stimulation (Morris et al, 2000). Accordingly, SRF was found to be increased after epileptic induction by pilocarpine (Nadler, 2003).…”

Section: Discussionmentioning

confidence: 99%

Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment

et al. 2016

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a b s t r a c tThe efficiency of most of the new antiepileptic drugs (AEDs) on clinical trials still falls short the success reported in pre-clinical studies, possibly because the validity of the animal models is insufficient to fully represent the human pathology. To improve the translational value for testing AEDs, we propose the use of non-human primates. Here, we suggest that triggering limbic seizures with low doses of PTZ in pilocarpine-treated marmosets might provide a more effective basis for the development of AED. Marmosets with epileptic background were more susceptible to seizures induced by PTZ, which were at least 3 times longer and more severe (about 6 times greater frequency of generalized seizures) in comparison to naïve peers. Accordingly, PTZ-induced seizures were remarkably less attenuated by AEDs in epileptic than naïve marmosets. While phenobarbital (40 mg/kg) virtually abolished seizures regardless of the animal's background, carbamazepine (120 mg/kg) and valproic acid (400 mg/kg) could not prevent PTZinduced seizures in epileptic animals with the same efficiency as observed in naïve peers. VPA was less effective regarding the duration of individual seizures in epileptic animals, as assessed in ECoG (p = 0.05). Similarly following CBZ treatment, the behavioral manifestation of generalized seizures lasted longer in epileptic (p < 0.05), which were also more frequent than in the naïve group (p < 0.05). As expected, epileptic marmosets experiencing stronger seizures showed more NPY-and FosB-immunostained neurons in a number of brain areas associated with the generation and spread of limbic seizures. Our results suggest that PTZ induced seizures over an already existing epileptic background constitutes a reliable and controllable mean for the screening of new AEDs.

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“…Briefly, hippocampi were homogenized and crude membranes were removed by centrifugation (Morris et al, 2000). Protein samples were balanced to 8 μg prior to gel loading.…”

Section: Western Blot Analysismentioning

confidence: 99%

Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus

et al. 2008

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SummaryAcquired epilepsy (AE) is characterized by spontaneous recurrent seizures and long-term changes that occur in surviving neurons following an injury such as status epilepticus (SE). Long-lasting alterations in hippocampal Ca 2+ homeostasis have been observed in both in vivo and in vitro models of AE. One major regulator of Ca 2+ homeostasis is the neuronal calcium binding protein, calbindinD28k that serves to buffer and transport Ca 2+ ions. This study evaluated the expression of hippocampal calbindin levels in the rat pilocarpine model of AE. Calbindin protein expression was reduced over 50% in the hippocampus in epileptic animals. This decrease was observed in the pyramidal layer of CA1, stratum lucidum of CA3, hilus, and stratum granulosum and stratum moleculare of the dentate gyrus when corrected for cell loss. Furthermore, calbindin levels in individual neurons were also significantly reduced. In addition, the expression of calbindin mRNA was decreased in epileptic animals. Time course studies demonstrated that decreased calbindin expression was initially present 1 month following pilocarpine-induced SE and lasted for up to 2 years after the initial episode of SE. The results indicate that calbindin is essentially permanently decreased in the hippocampus in AE. This decrease in hippocampal calbindin may be a major contributing factor underlying some of the plasticity changes that occur in epileptogenesis and contribute to the alterations in Ca 2+ homeostasis associated with AE.

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Chronic ΔFosB expression and increased AP-1 transcription factor binding are associated with the long term plasticity changes in epilepsy

Cited by 56 publications

References 39 publications

Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsy

Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsy

Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment

Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus

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