Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction

Goldberg, Ethan M.; Coulter, Douglas A.

doi:10.1038/nrn3482

Cited by 419 publications

(313 citation statements)

References 173 publications

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“…WT and HET Martinotti cells had indistinguishable input resistance, membrane capacitance, and resting membrane potential (Table 1). In current-clamp recordings, WT Martinotti cells displayed a low discharge rate and typical AP frequency accommodation in response to incremental steps of current injection (1 s), as previously reported (27,28,32,33) (Fig. 4B).…”

Section: Impaired Monosynaptic Transmission Between Layer V Pyramidalmentioning

confidence: 69%

Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome

Tai

Abe

Westenbroek

et al. 2014

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

227

215

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Haploinsufficiency of the voltage-gated sodium channel Na V 1.1 causes Dravet syndrome, an intractable developmental epilepsy syndrome with seizure onset in the first year of life. Specific heterozygous deletion of Na V 1.1 in forebrain GABAergic-inhibitory neurons is sufficient to cause all the manifestations of Dravet syndrome in mice, but the physiological roles of specific subtypes of GABAergic interneurons in the cerebral cortex in this disease are unknown. Voltage-clamp studies of dissociated interneurons from cerebral cortex did not detect a significant effect of the Dravet syndrome mutation on sodium currents in cell bodies. However, current-clamp recordings of intact interneurons in layer V of neocortical slices from mice with haploinsufficiency in the gene encoding the Na V 1.1 sodium channel, Scn1a, revealed substantial reduction of excitability in fast-spiking, parvalbumin-expressing interneurons and somatostatin-expressing interneurons. The threshold and rheobase for action potential generation were increased, the frequency of action potentials within trains was decreased, and action-potential firing within trains failed more frequently. Furthermore, the deficit in excitability of somatostatin-expressing interneurons caused significant reduction in frequency-dependent disynaptic inhibition between neighboring layer V pyramidal neurons mediated by somatostatin-expressing Martinotti cells, which would lead to substantial disinhibition of the output of cortical circuits. In contrast to these deficits in interneurons, pyramidal cells showed no differences in excitability. These results reveal that the two major subtypes of interneurons in layer V of the neocortex, parvalbumin-expressing and somatostatin-expressing, both have impaired excitability, resulting in disinhibition of the cortical network. These major functional deficits are likely to contribute synergistically to the pathophysiology of Dravet syndrome. D ravet syndrome (DS), also referred to as "severe myoclonic epilepsy in infancy," is a rare genetic epileptic encephalopathy characterized by frequent intractable seizures, severe cognitive deficits, and premature death (1-3). DS is caused by loss-of-function mutations in SCN1A, the gene encoding type I voltage-gated sodium channel Na V 1.1, which usually arise de novo in the affected individuals (4-7). Like DS patients, mice with heterozygous lossof-function mutations in Scn1a exhibit ataxia, sleep disorder, cognitive deficit, autistic-like behavior, and premature death (8)(9)(10)(11)(12)(13)(14). Like DS patients, DS mice first become susceptible to seizures caused by elevation of body temperature and subsequently experience spontaneous myoclonic and generalized tonic-clonic seizures (11). Global deletion of Na V 1.1 impairs Na + currents and action potential (AP) firing in GABAergic-inhibitory interneurons (8-10), and specific deletion of Na V 1.1 in forebrain interneurons is sufficient to cause DS in mice (13,15). These data suggest that the loss of interneuron excitability and resulting di...

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Section: Impaired Monosynaptic Transmission Between Layer V Pyramidalmentioning

confidence: 69%

Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome

Tai

Abe

Westenbroek

et al. 2014

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

227

215

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“…; e.g. Repressor element 1-silencing transcription (REST) factor pathway negatively regulates the expression of several genes including these for HCN1-4 channels (Goldberg and Coulter, 2013;Roopra et al, 2012) which have been involved in the development of absence seizures in this strain (see Section 3.3) among others.…”

Section: Current Limitations and Future Directionsmentioning

confidence: 99%

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

Russo

Citraro

Constanti³

et al. 2016

Neuroscience & Biobehavioral Reviews

128

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Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development.Neuroscience and Biobehavioral Reviews http://dx.doi.org/10. 1016/j.neubiorev.2016.09.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe WAG/Rij rat model has recently gathered attention as a suitable animal model of absence epileptogenesis. This latter term has a broad definition encompassing any possible cause that determines the development of spontaneous seizures; however, most of, if not all, preclinical knowledge on epileptogenesis is confined to the study of post-brain insult models such as traumatic brain injury or post-status epilepticus models. WAG/Rij rats, but also synapsin 2 knockout, Kv7 current-deficient mice represent the first examples of genetic models where an efficacious antiepileptogenic treatment (ethosuximide) was started before seizure onset. In this review, we have critically reconsidered all articles published regarding WAG/Rij rats, from the perspective that the period before SWD onset is considered as the latent period. In our new theory on seizure development, it is proposed that genes might be considered as the initial "insult" responsible for all plastic changes underpinning the development of spontaneous seizures. According to this idea, in WAG/Rij rats, genetic predisposition would lead to the development of abnormal bilateral cortical epileptic foci, which would then nongenetically stimulate the rest of the brain to rearrange networks in order to phenotypically develop seizures similarly to what happens during electrical kindling.

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“…Although we cannot completely exclude the occurrence of two independent events in this patient, his perinatal history and the area of the lesion, which is consistent with the focus of the epileptic EEG abnormalities both in the neonatal period and later in life, strongly suggest that he suffered from PNE after a perinatal stroke. Epilepsy is a common endpoint of many forms of acquired brain pathology (Goldberg and Coulter, 2013). Brain injuries are often followed by a latent period of variable duration before the appearance of epilepsy.…”

Section: Discussionmentioning

confidence: 99%

A 15-year epileptogenic period after perinatal brain injury

Pisani¹

2017

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SummarySeizures are a frequent acute neurological event in the neonatal period. Up to 12 to 18% of all seizures in newborns are due to perinatal stroke and up to 39% of affected children can then develop epilepsy in childhood. We report the case of a young patient who presented stroke-related seizures in the neonatal period and then developed focal symptomatic epilepsy at 15 years of age, and in whom the epileptic focus was found to co-localize with the site of his ischemic brain lesion. Such a prolonged silent period before onset of remote symptomatic epilepsy has not previously been reported. This case suggests that newborns with seizures due to a neonatal stroke are at higher risk of epilepsy and that the epileptogenic process in these subjects can last longer than a decade.

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Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction

Cited by 419 publications

References 173 publications

Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome

Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

A 15-year epileptogenic period after perinatal brain injury

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