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BRAIN

A JOURNAL OF NEUROLOGY

Electroclinical characterization of epileptic

seizures in leucine-rich, glioma-inactivated

1-deﬁcient mice

Elodie Chabrol,

Vincent Navarro,

1,2

Giovanni Provenzano,

1,3

Ivan Cohen,

line Dinocourt,

Sophie Rivaud-Pe

choux,

Desdemona Fricker,

Michel Baulac,

1,2

Richard Miles,

Eric LeGuern

1,4

and Ste

phanie Baulac

1 CRICM UPMC/INSERM UMR_S975/CNRS UMR7225, Ho

pital de la Pitie

-Salpe

trie

re, 75013 Paris, France

2 Epileptology unit, AP-HP, Ho

pital de la Pitie

-Salpe

trie

re, 75013 Paris, France

3 Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, 87050 Cosenza, Italy

4De

partement de Ge

tique et Cytoge

tique, AP-HP, Ho

pital de la Pitie

-Salpe

trie

re, 75013 Paris, France

Correspondence to: Ste

phanie Baulac,

CRICM UMR_S975,

pital de la Pitie

-Salpe

trie

re,

timent Pharmacie,

47 Bd de l’ho

pital,

75013 Paris, France

E-mail: [email protected]

Mutations of the

LGI1

(

leucine-rich, glioma-inactivated 1

) gene underlie autosomal dominant lateral temporal lobe epilepsy, a

focal idiopathic inherited epilepsy syndrome. The

LGI1

gene encodes a protein secreted by neurons, one of the only non-ion

channel genes implicated in idiopathic familial epilepsy. While mutations probably result in a loss of function, the role of LGI1

in the pathophysiology of epilepsy remains unclear. Here we generated a germline knockout mouse for LGI1 and examined

spontaneous seizure characteristics, changes in threshold for induced seizures and hippocampal pathology. Frequent spontan-

eous seizures emerged in homozygous LGI1

/

mice during the second postnatal week. Properties of these spontaneous events

were examined in a simultaneous video and intracranial electroencephalographic recording. Their mean duration was 120  12 s,

and behavioural correlates consisted of an initial immobility, automatisms, sometimes followed by wild running and tonic

and/or clonic movements. Electroencephalographic monitoring indicated that seizures originated earlier in the hippocampus

than in the cortex. LGI1

/

mice did not survive beyond postnatal day 20, probably due to seizures and failure to feed. While no

major developmental abnormalities were observed, after recurrent seizures we detected neuronal loss, mossy ﬁbre sprouting,

astrocyte reactivity and granule cell dispersion in the hippocampus of LGI1

/

mice. In contrast, heterozygous LGI1

+/

litter-

mates displayed no spontaneous behavioural epileptic seizures, but auditory stimuli induced seizures at a lower threshold,

reﬂecting the human pathology of sound-triggered seizures in some patients. We conclude that LGI1

+/

and LGI1

/

mice may

provide useful models for lateral temporal lobe epilepsy, and more generally idiopathic focal epilepsy.

Keywords: autosomal dominant lateral temporal epilepsy; temporal lobe epilepsy; audiogenic; monogenic

Abbreviations: ADAM = postsynaptic disintegrin and metalloproteinase domain; ADLTE = autosomal dominant lateral temporal

epilepsy; LGI1 = leucine-rich, glioma-inactivated 1

doi:10.1093/brain/awq171 Brain 2010: 133; 2749–2762 | 2749

Received April 5, 2010. Revised May 9, 2010. Accepted May 14, 2010. Advance Access publication July 21, 2010

ß The Author(s) 2010. Published by Oxford University Press on behalf of Brain.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5),

which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Summary of Contents

Page 1 - 1-deﬁcient mice

BRAINA JOURNAL OF NEUROLOGYElectroclinical characterization of epilepticseizures in leucine-rich, glioma-inactivated1-deﬁcient miceElodie Chabrol,1Vin

Page 2 - Introduction

neurons varied among LGI1/mice, highlighting the importanceof seizure number and severity in neuronal degeneration.DiscussionWe report the electrocl

Page 3

the temporal structures. We note that some patients with ADLTEdescribe psychic (‘de´ja`-vu’) and autonomous symptoms (epigastricsensations), character

Page 4 - Homozygous LGI1

are typical for patients with temporal lobe epilepsies as well asnumerous animal models of hippocampal seizures (Dudek andSutula, 2007). No such morph

Page 5

patients with pharmacoresistant epilepsies, including but not lim-ited to those with LGI1 mutations, by identifying new pre- andpostsynaptic targets f

Page 6

Di Bonaventura C, Carni M, Diani E, Fattouch J, Vaudano EA, Egeo G,et al. Drug resistant ADLTE and recurrent partial status epilepticus withdysphasic

Page 7

IntroductionNearly all mutated genes that have been linked to monogenicidiopathic epilepsies code for components of ion channels or neuro-transmitter

Page 8 - Adult heterozygous LGI1

antibody (ab30868; 1 mg/ml; Abcam), rabbit polyclonal anti-LGI1antibody (sc-28238 H56; 1 mg/ml; Santa Cruz) and monoclonal anti-tubulin antibody (1/2

Page 9

Homozygous LGI1/mice displayearly onset spontaneous seizuresThe behaviour and appearance of LGI1/mice at birth did notdiffer from that of LGI1+/a

Page 10 - Discussion

jerks; (ii) hyperkinetic running, often with repeated, large clonicsof all limbs and frequently incontinence and loss of postural equi-librium; and (i

Page 11 - CA1CA3Hipp

postnatal days 11 and 15, within the cortex and/or hippocampus(Fig. 4B).The percentage of mice showing electroclinical seizures reacheda peak at postn

Page 12 - Heterozygous LGI1

1000 μV1 secCxHpHpCxHpHp1000 μV1 secDFG1 secCxHpHp1000 μV1 secCxHpHp12 3A41000 μVCxHpHp1000 μV1 secECxHpHpC1000 μV1 secCxHpHpBCxHpHp1000 μV1 secCxHpHp

Page 13 - References

No LGI1-null mice survived beyond postnatal day 21 (Fig. 5A),while no LGI1+/or wild-type littermates had died at this age.We noted at postnatal day 1

Page 14

Seizure-induced brain damage inhomozygous LGI1/miceNo major differences in cortical or hippocampal organization wereevident in Nissl-stained section

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