Abstract:
OBJECTIVE:Deletions of CACNA1A, encoding the α1 subunit of CaV 2.1 channels, cause epilepsy with ataxia in humans. Whereas the deletion of Cacna1a in γ-aminobutyric acidergic (GABAergic) interneurons (INs) derived from the medial ganglionic eminence (MGE) impairs cortical inhibition and causes generalized seizures in Nkx2.1Cre ;Cacna1ac/c mice, the targeted deletion of Cacna1a in somatostatin-expressing INs (SOM-INs), a subset of MGE-derived INs, does not result in seizures, indicating a crucial role of parvalbumin-expressing (PV) INs. Here we identify the cellular and network consequences of Cacna1a deletion specifically in PV-INs. METHODS:We generated PVCre ;Cacna1ac/c mutant mice carrying a conditional Cacna1a deletion in PV neurons and evaluated the cortical cellular and network outcomes of this mutation by combining immunohistochemical assays, in vitro electrophysiology, 2-photon imaging, and in vivo video-electroencephalographic recordings. RESULTS:PVCre ;Cacna1ac/c mice display reduced cortical perisomatic inhibition and frequent absences but only rare motor seizures. Compared to Nkx2.1Cre ;Cacna1ac/c mice, PVCre ;Cacna1ac/c mice have a net increase in cortical inhibition, with a gain of dendritic inhibition through sprouting of SOM-IN axons, largely preventing motor seizures. This beneficial compensatory remodeling of cortical GABAergic innervation is mTORC1-dependent and its inhibition with rapamycin leads to a striking increase in motor seizures. Furthermore, we show that a direct chemogenic activation of cortical SOM-INs prevents motor seizures in a model of kainate-induced seizures. INTERPRETATION:Our findings provide novel evidence suggesting that the remodeling of cortical inhibition, with an mTOR-dependent gain of dendritic inhibition, determines the seizure phenotype in generalized epilepsy and that mTOR inhibition can be detrimental in epilepsies not primarily due to mTOR hyperactivation. Ann Neurol 2018;84:436-451.
journal_name
Ann Neuroljournal_title
Annals of neurologyauthors
Jiang X,Lupien-Meilleur A,Tazerart S,Lachance M,Samarova E,Araya R,Lacaille JC,Rossignol Edoi
10.1002/ana.25301subject
Has Abstractpub_date
2018-09-01 00:00:00pages
436-451issue
3eissn
0364-5134issn
1531-8249journal_volume
84pub_type
杂志文章abstract::We measured neurotransmitter markers in autopsied brain of infants with glycine encephalopathy (GE). Because patients with GE develop intractable seizures, special attention was devoted to those neurotransmitter systems implicated in human epilepsy. Mean levels of glycine in the frontal cortex of GE patients were thre...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410240319
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abstract::A patient is described who suffered a bilateral hemorrhagic infarction in the parasagittal cerebrum following neonatal asphyxia. This case confirms experimental results that show the parasagittal cerebrum is especially vulnerable to ischemic damage in newborns. ...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410210215
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abstract::A chronic remitting-relapsing form of experimental allergic encephalomyelitis (EAE) has been produced in monkeys sensitized to homologous myelin basic protein in Freund's complete adjuvants by the technique of suboptimal treatment after the onset of disease. Not only does the clinical course resemble that of human mul...
journal_title:Annals of neurology
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doi:10.1002/ana.410240608
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journal_title:Annals of neurology
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doi:10.1002/ana.22389
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pub_type: 杂志文章,多中心研究
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journal_title:Annals of neurology
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doi:10.1002/ana.410220111
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abstract::Magnetic resonance imaging (MRI) provides a powerful tool for assessing disease activity in multiple sclerosis (MS), and its role as a surrogate marker for monitoring treatment efficacy is now becoming established. The most commonly used MRI parameters in treatment trials are (1) monthly gadolinium-enhanced MRI, with ...
journal_title:Annals of neurology
pub_type: 杂志文章,评审
doi:10.1002/ana.410430311
更新日期:1998-03-01 00:00:00
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journal_title:Annals of neurology
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doi:10.1002/ana.410290119
更新日期:1991-01-01 00:00:00
abstract:OBJECTIVE:Infantile spasms are seizures associated with a severe epileptic encephalopathy presenting in the first 2 years of life, and optimal treatment continues to be debated. This study evaluates early and sustained response to initial treatments and addresses both clinical remission and electrographic resolution of...
journal_title:Annals of neurology
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doi:10.1002/ana.24594
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410030405
更新日期:1978-04-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/1531-8249(199902)45:2<182::aid-ana8>3.0.co
更新日期:1999-02-01 00:00:00
abstract::Inborn errors of urea synthesis can present in the newborn period as a catastrophic illness or later in childhood or adulthood with an indolent course punctuated by hyperammonemic episodes. Because symptoms mimic other neuropsychiatric disorders, it is common for there to be a delay in diagnosis, often with dire conse...
journal_title:Annals of neurology
pub_type: 杂志文章,评审
doi:10.1002/ana.410350204
更新日期:1994-02-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章,多中心研究
doi:10.1002/ana.25669
更新日期:2020-03-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410140106
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.10357
更新日期:2002-11-01 00:00:00
abstract::Knowledge about the balance between heritable and nonheritable risk in multiple sclerosis (MS) is based on twin studies in high-prevalence areas. In a study that avoided ascertainment limitations and directly compared continental Italy (medium-prevalence) and Sardinia (high-prevalence), we ascertained 216 pairs from 3...
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pub_type: 杂志文章
doi:10.1002/ana.20683
更新日期:2006-01-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:
更新日期:2001-03-01 00:00:00
abstract::A 26-year-old woman was in spontaneous clinical remission from myasthenia gravis (MG) for six months, yet gave birth to a full-term infant with typical neonatal MG. It is believed that transplacental transfer of anti-acetylcholine (ACh) receptor antibodies is responsible for neonatal MG; therefore, neonatal MG represe...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410060119
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410270517
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doi:10.1002/ana.25827
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journal_title:Annals of neurology
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doi:10.1002/ana.410410416
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410040515
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410080404
更新日期:1980-10-01 00:00:00
abstract::Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimer's disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimer's disease patients, and control subjects. The temporal lobe struct...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:
更新日期:2001-04-01 00:00:00
abstract::Regional cerebral blood flow (rCBF) was measured in human subjects during saccadic eye movements by a 254-channel dynamic gamma camera. Focal rCBF increases were repeatedly observed in an area within the middle precentral and premotor regions which corresponds to the frontal eye field in humans. Our findings suggest t...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410050112
更新日期:1979-01-01 00:00:00
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journal_title:Annals of neurology
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doi:10.1002/ana.23733
更新日期:2012-09-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410350422
更新日期:1994-04-01 00:00:00
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pub_type: 杂志文章,评审
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410340211
更新日期:1993-08-01 00:00:00