Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy

Cossart, Rosa; Dinocourt, Céline; Hirsch, J F; Merchán-Pérez, Ángel; Felipe, Javier De; Ben-Ari, Yehezkel; Esclapez, Monique; Bernard, Christophe

doi:10.1038/82900

Cited by 524 publications

(433 citation statements)

References 48 publications

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“…In theory, the loss of neurons, especially GABAergic interneurons, would account nicely for the neuronal hyperexcitability in epilepsy (Sloviter, 1987;Morin et al, 1998;Cossart et al, 2001). In this study, although NR2A and NR2B antagonists offered similar degrees of neuroprotection, only NR2A antagonist prevented epileptogenesis.…”

Section: Discussionmentioning

confidence: 49%

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

Qian

He²,

Hu³

et al. 2007

J. Neurosci.

144

103

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Fleeting activation of NMDA receptors (NMDARs) induces long-term modification of synaptic connections and refinement of neuronal circuits, which may underlie learning and memory and contribute to pathogenesis of a diversity of neurological diseases, including epilepsy. Here, we found that NR2A and NR2B subunit-containing NMDARs were coupled to distinct intracellular signaling, resulting in differential BDNF expression and extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Selective activation of NR2A-containing NMDARs increased BDNF gene expression. Activation of NR2B-containing NMDARs led to ERK1/2 phosphorylation. Furthermore, selectively blocking NR2A-containing NMDARs impaired epileptogenesis and the development of mossy fiber sprouting in the kindling and pilocarpine rat models of limbic epilepsy, whereas inhibiting NR2B-containing NMDARs had no effects in epileptogenesis and mossy fiber sprouting. Interestingly, blocking either NR2A- or NR2B-containing NMDARs decreased status epilepticus-induced neuronal cell death. The specific requirement of NR2A and its downstream signaling for epileptogenesis implicates attractive new targets for the development of drugs that prevent epilepsy in patients with brain injury.

show abstract

Section: Discussionmentioning

confidence: 49%

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

Qian

He²,

Hu³

et al. 2007

J. Neurosci.

144

103

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“…It has been shown previously that activation of the temporoammonic pathway can generate a burst of action potentials in pilocarpine-treated animals, demonstrating facilitation of the direct excitatory pathway from the entorhinal cortex in epilepsy (Cossart et al, 2001;Wozny et al, 2005). However, to our knowledge, no other study has quantified directly the relative degree of circuit disruption in multiple hippocampal pathways from the same epileptic animals, particularly at the spatial and temporal resolution made possible by high-speed voltage-sensitive dye imaging.…”

Section: Discussionmentioning

confidence: 80%

Massive and Specific Dysregulation of Direct Cortical Input to the Hippocampus in Temporal Lobe Epilepsy

Ang

Carlson²,

Coulter³

2006

J. Neurosci.

135

115

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Epilepsy affects 1-2% of the population, with temporal lobe epilepsy (TLE) the most common variant in adults. Clinical and experimental studies have demonstrated hippocampal involvement in the seizures underlying TLE. However, identification of specific functional deficits in hippocampal circuits associated with possible roles in seizure generation remains controversial. Significant attention has focused on anatomic and cellular alterations in the dentate gyrus. The dentate gyrus is a primary gateway regulating cortical input to the hippocampus and, thus, a possible contributor to the aberrant cortical-hippocampal interactions underlying the seizures of TLE. Alternate cortical pathways innervating the hippocampus might also contribute to seizure initiation. Despite this potential importance in TLE, these pathways have received little study. Using simultaneous voltage-sensitive dye imaging and patch-clamp recordings in slices from animals with epilepsy, we assessed the relative degree of synaptic excitation activated by multiple cortical inputs to the hippocampus. Surprisingly, dentate gyrus-mediated regulation of the relay of cortical input to the hippocampus is unchanged in epileptic animals, and input via the Schaffer collaterals is actually decreased despite reduction in Schaffer-evoked inhibition. In contrast, a normally weak direct cortical input to area CA1 of hippocampus, the temporoammonic pathway, exhibits a TLE-associated transformation from a spatially restricted, highly regulated pathway to an excitatory projection with Ͼ10-fold increased effectiveness. This dysregulated temporoammonic pathway is critically positioned to mediate generation and/or propagation of seizure activity in the hippocampus.

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“…The loss of SOM interneurons in the dentate gyrus after SE has been found in electrical stimulation models [31] , KA models [48] and pilo carpine-induced epileptic rats [49] . In one study with the pilocarpine model, there was a 46% loss of SOM-containing interneurons in the stratum oriens of the CA1 area [50] . The loss of SOM-positive hilar neurons in TLE is likely to substantially reduce inhibitory synaptic input to granule cells.…”

Section: Neuropeptide-containing Interneurons and Epilepsymentioning

confidence: 99%

Dysfunction of hippocampal interneurons in epilepsy

Liu

et al. 2014

Neurosci. Bull.

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Gamma-amino-butyric acid (GABA)-containing interneurons are crucial to both development and function of the brain. Down-regulation of GABAergic inhibition may result in the generation of epileptiform activity. Loss, axonal sprouting, and dysfunction of interneurons are regarded as mechanisms involved in epileptogenesis. Recent evidence suggests that network connectivity and the properties of interneurons are responsible for excitatory-inhibitory neuronal circuits. The balance between excitation and inhibition in CA1 neuronal circuitry is considerably altered during epileptic changes. This review discusses interneuron diversity, the causes of interneuron dysfunction in epilepsy, and the possibility of using GABAergic neuronal progenitors for the treatment of epilepsy.

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Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy

Cited by 524 publications

References 48 publications

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

Massive and Specific Dysregulation of Direct Cortical Input to the Hippocampus in Temporal Lobe Epilepsy

Dysfunction of hippocampal interneurons in epilepsy

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