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The presynaptic active zone protein RIM1? controls epileptogenesis following status epilepticus.

ABSTRACT: To ensure operation of synaptic transmission within an appropriate dynamic range, neurons have evolved mechanisms of activity-dependent plasticity, including changes in presynaptic efficacy. The multidomain protein RIM1? is an integral component of the cytomatrix at the presynaptic active zone and has emerged as key mediator of presynaptically expressed forms of synaptic plasticity. We have therefore addressed the role of RIM1? in aberrant cellular plasticity and structural reorganization after an episode of synchronous neuronal activity pharmacologically induced in vivo [status epilepticus (SE)]. Post-SE, all animals developed spontaneous seizure events, but their frequency was dramatically increased in RIM1?-deficient mice (RIM1?(-/-)). We found that in wild-type mice (RIM1?(+/+)) SE caused an increase in paired-pulse facilitation in the CA1 region of the hippocampus to the level observed in RIM1?(-/-) mice before SE. In contrast, this form of short-term plasticity was not further enhanced in RIM1?-deficient mice after SE. Intriguingly, RIM1?(-/-) mice showed a unique pattern of selective hilar cell loss (i.e., endfolium sclerosis), which so far has not been observed in a genetic epilepsy animal model, as well as less severe astrogliosis and attenuated mossy fiber sprouting. These findings indicate that the decrease in release probability and altered short- and long-term plasticity as present in RIM1?(-/-) mice result in the formation of a hyperexcitable network but act in part neuroprotectively with regard to neuropathological alterations associated with epileptogenesis. In summary, our results suggest that presynaptic plasticity and proper function of RIM1? play an important part in a neuron's adaptive response to aberrant electrical activity.

SUBMITTER: Pitsch J

PROVIDER: S-EPMC6621253 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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The presynaptic active zone protein RIM1α controls epileptogenesis following status epilepticus.

Pitsch Julika J Opitz Thoralf T Borm Verena V Woitecki Anne A Staniek Matthäus M Beck Heinz H Becker Albert J AJ Schoch Susanne S

The Journal of neuroscience : the official journal of the Society for Neuroscience 20120901 36

To ensure operation of synaptic transmission within an appropriate dynamic range, neurons have evolved mechanisms of activity-dependent plasticity, including changes in presynaptic efficacy. The multidomain protein RIM1α is an integral component of the cytomatrix at the presynaptic active zone and has emerged as key mediator of presynaptically expressed forms of synaptic plasticity. We have therefore addressed the role of RIM1α in aberrant cellular plasticity and structural reorganization after ...[more]

PMID: 22956829

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Project description:ObjectiveExposure to chemical warfare nerve agents (CWNAs), such as soman (GD), can induce status epilepticus (SE) that becomes refractory to benzodiazepines when treatment is delayed, leading to increased risk of epileptogenesis, severe neuropathology, and long-term behavioral and cognitive deficits. Rodent models, widely used to evaluate novel medical countermeasures (MCMs) against CWNA exposure, normally express plasma carboxylesterase, an enzyme involved in the metabolism of certain organophosphorus compounds. To better predict the efficacy of novel MCMs against CWNA exposure in human casualties, it is crucial to use appropriate animal models that mirror the human condition. We present a comprehensive characterization of the seizurogenic, epileptogenic, and neuropathologic effects of GD exposure with delayed anticonvulsant treatment in the plasma carboxylesterase knockout (ES1-/-) mouse.MethodsElectroencephalography (EEG) electrode-implanted ES1-/- and wild-type (C57BL/6) mice were exposed to various seizure-inducing doses of GD, treated with atropine sulfate and the oxime HI-6 at 1 minute after exposure, and administered midazolam at 15-30 minutes following the onset of seizure activity. The latency of acute seizure onset and spontaneous recurrent seizures (SRS) was assessed, as were changes in EEG power spectra. At 2 weeks after GD exposure, neurodegeneration and neuroinflammation were assessed.ResultsGD-exposed ES1-/- mice displayed a dose-dependent response in seizure severity. Only ES1-/- mice exposed to the highest tested dose of GD developed SE, subchronic alterations in EEG power spectra, and SRS. Degree of neuronal cell loss and neuroinflammation were dose-dependent; no significant neuropathology was observed in C57BL/6 mice or ES1-/- mice exposed to lower GD doses.SignificanceThe US Food and Drug Administration (FDA) animal rule requires the use of relevant animal models for the advancement of MCMs against CWNAs. We present evidence that argues for the use of the ES1-/- mouse model to screen anticonvulsant, antiepileptic, and/or neuroprotective drugs against GD-induced toxicity, as well as to identify mechanisms of GD-induced epileptogenesis.

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The presynaptic active zone protein RIM1? controls epileptogenesis following status epilepticus.

Publications

The presynaptic active zone protein RIM1α controls epileptogenesis following status epilepticus.

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