Audiogenic Seizures - Biological Phenomenon and Experimental Model of Human Epilepsies

The NMDA receptor-mediated Ca2+ signaling during simultaneous pre- and postsynaptic activity is critically involved in synaptic plasticity and thus has a key role in the nervous system. In GRIN2-variant patients alterations of this coincidence detection provoked complex clinical phenotypes, ranging from reduced muscle strength to epileptic seizures and intellectual disability. By using our gene-targeted mouse line (Grin2aN615S), we show that voltage-independent glutamate-gated signaling of GluN2A-containing NMDA receptors is associated with NMDAR-dependent audiogenic seizures due to hyperexcitable midbrain circuits. In contrast, the NMDAR antagonist MK-801-induced c-Fos expression is reduced in the hippocampus. Likewise, the synchronization of theta- and gamma oscillatory activity is lowered during exploration, demonstrating reduced hippocampal activity. This is associated with exploratory hyperactivity and aberrantly increased and dysregulated levels of attention that can interfere with associative learning, in particular when relevant cues and reward outcomes are disconnected in space and time. Together, our findings provide (i) experimental evidence that the inherent voltage-dependent Ca2+ signaling of NMDA receptors is essential for maintaining appropriate responses to sensory stimuli and (ii) a mechanistic explanation for the neurological manifestations seen in the NMDAR-related human disorders with GRIN2 variant-meidiated intellectual disability and focal epilepsy.

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Audiogenic Epilepsy -- The Pathological Neural Net and Genetic Predisposition

Федотова

Сурина

Pospelov

et al. 2012

2012 International Conference on Biomedical Engineering and Biotechnology

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The paper is the minireview of the main data concerning the functional properties of rodent audiogenic epilepsy (AE) in rats of inbred strain Krushinsky-Molodkina -KM (Moscow, Russia). These data demonstrate that the genetically determined abnormal functions of CNS (presumably in brainstem neural circuits) which are the cause of AE could be responsible not only for the clonic and tonic seizures in response to loud sound but for the postictal cataleptic state as well. After AE seizure fit the brain stem acoustic evoked potentials changes, probably due to inactivation of inferior colliculi. AE is the valuable model for the preclinical investigation of new pharmacological agents and for study the intrinsic mechanisms of the epileptogenesis.

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Audiogenic Seizures - Biological Phenomenon and Experimental Model of Human Epilepsies

Cited by 4 publications

References 138 publications

Characteristics of the Functional State of the Hypothalamo-Hypophyseal-Adrenocortical System in Krushinskii–Molodkina Rats

Characteristics of the Functional State of the Hypothalamo-Hypophyseal-Adrenocortical System in Krushinskii–Molodkina Rats

Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice

Audiogenic Epilepsy -- The Pathological Neural Net and Genetic Predisposition

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