Wavetek 131A Bedienungsanleitung PDF herunterladen (Seite 13)

patients with pharmacoresistant epilepsies, including but not lim-

ited to those with LGI1 mutations, by identifying new pre- and

postsynaptic targets for modulation of circuit excitability by LGI1.

LGI1-deﬁcient mouse: a tool to

understand the function of LGI1

The LGI1 knockout mouse may help understand the function of

this secreted neuronal protein. While the loss of both LGI1 alleles

by somatic mutations in glioma cell lines was ﬁrst thought to con-

tribute to malignant brain tumours (Chernova et al. , 1998), our

ﬁndings emphasize a role in epileptogenesis. Since we found no

evidence for gliomas in LGI1

/

Nissl-stained brains sections

(n = 8), the germinal loss of LGI1 seems unlikely to be related to

brain tumour genesis. While tumours might conceivably develop in

LGI1

/

mice if they did not die prematurely, there is no evidence

for an elevated rate of malignancy in families with ADLTE

(Brodtkorb et al., 2003).

Recent data have shown that LGI1 shapes neuronal morphology

at multiple levels. It forms part of canonical pathways controlling

axon guidance (Kunapuli et al., 2009), hippocampal neurite out-

growth in vitro (Owuor et al., 2009) and postnatal pruning of

granule cell dendrites and glutamatergic synapses (Zhou et al.,

2009). Possibly developmental actions of LGI1 on dendritic and

synaptic maturation contribute to epileptogenesis. We detected no

major anomalies in cortical lamination in either LGI1

/

or LGI1

+/

mice, but further work is needed to deﬁne more subtle morpho-

logical changes.

We consistently observed that recurrent seizures were ﬁrst

initiated at postnatal day 10 in LGI1

/

mice. This date of

onset was not correlated with the developmental pattern of

LGI1 expression. In the wild-type mouse, the antibody we used

(ab30868; speciﬁcity proven, since there was no LGI1 signal in

tissue from knockout mice) detected LGI1 as early as embryonic

day 16, somewhat earlier than previous studies (Furlan et al.,

2006; Ribeiro et al., 2008; Zhou et al., 2009). This onset timing

of seizures, loss of body weight and premature death in LGI1

/

mice mirrors that in SCN1A knockout and knock-in mice, which

are models for severe myoclonic epilepsy of infancy (Yu et al.,

2006; Ogiwara et al., 2007). Many signiﬁcant developmental

events occur in rodents during the restricted time window when

seizures emerge in LGI1

/

mice, including the switch in polarity

of GABAergic signalling in inhibitory interneurons (Ben-Ari and

Holmes, 2006) and the maturation of excitatory synapses termi-

nating on principal cells of the cortex and hippocampus (Zhou

et al., 2009).

Recent reports converge to show that LGI1 regulates the devel-

opment of glutamatergic synapses (Fukata et al., 2010; Yu et al.,

2010) and yet contradict each other. Yu et al. (2010) suggest that

an absence of LGI1 enhances excitatory synaptic transmission with

an increased frequency of excitatory postsynaptic synaptic currents

but no difference in their amplitude (Yu et al., 2010). In contrast,

Fukata and colleagues (2010) found a reduction in the amplitude

of excitatory postsynaptic synaptic currents (selectively of

AMPA-mediated excitatory postsynaptic synaptic currents), but

no change in their frequency (Fukata et al., 2010). Further studies

may reveal the reasons for this difference.

It remains unclear how mutations in or inactivation of LGI1 led

to epilepsy. Possibly, temporally restricted deletion of LGI1 using

inducible Cre transgenic mice may permit the differentiation of

defects in synaptic transmission and/or cellular excitability due to

prenatal or postnatal neuronal development, and those due to a

lack of LGI1 in the adult. LGI1 is a novel type of epilepsy gene,

structurally distinct from ion channel genes involved in other in-

herited epilepsies. The human ADLTE syndrome may therefore

depend on a pathway to enhanced brain excitability different

from those resulting from altered ion channels.

Acknowledgements

The mouse mutant line was established at the Mouse Clinical

Institute—Institut Clinique de la Souris (Illkirch, France). We

would like to thank Jerome Garrigue for genotyping, Annick

Prigent for immunohistochemistry, Philippe Couarch for technical

help and Isabelle Gourﬁnkel-An and Ste

phanie Millecamps for

helpful discussion. We are also grateful to Revital Rattenbach for

kindly providing the PGK-Cre mouse line and Richard Palmiter for

offering the anti-ZnT3 antibody.

Funding

Fondation pour la Recherche sur le Cerveau (FRC); FP6 Integrated

Project EPICURE; Sanoﬁ-Aventis; Japan Society of the Promotion

of Sciences (to S.B.); Ile de France (to E.C.); Contrat d’interface

INSERM (to V.N.) and Agence Nationale de la Recherche

(ANR-08-MNP-013 to C.D.). Funding to pay the Open Access

publication charges for this article was provided by Fondation

pour la Rechercher Medicale.

Supplementary material

Supplementary material is available at Brain online.

References

Baulac S, Baulac M. Advances on the genetics of mendelian idiopathic

epilepsies. Neurol Clin 2009; 27: 1041–61.

Ben-Ari Y, Holmes GL. Effects of seizures on developmental processes in

the immature brain. Lancet Neurol 2006; 5: 1055–63.

Brodtkorb E, Nakken KO, Steinlein OK. No evidence for a seriously

increased malignancy risk in LGI1-caused epilepsy. Epilepsy Res

2003; 56: 205–8.

Chabrol E, Popescu C, Gourﬁnkel-An I, Trouillard O, Depienne C,

Senechal K, et al. Two novel epilepsy-linked mutations leading to a

loss of function of LGI1. Arch Neurol 2007; 64: 217–22.

Chernova OB, Somerville RP, Cowell JK. A novel gene, LGI1, from

10q24 is rearranged and downregulated in malignant brain tumors.

Oncogene 1998; 17: 2873–81.

de Bellescize J, Boutry N, Chabrol E, Andre-Obadia N, Arzimanoglou A,

Leguern E, et al. A novel three base-pair LGI1 deletion leading to loss

of function in a family with autosomal dominant lateral temporal

epilepsy and migraine-like episodes. Epilepsy Res 2009; 85: 118–22.

LGI1 knockout mice Brain 2010: 133; 2749–2762 | 2761

by guest on May 15, 2015Downloaded from

1 2 ... 8 9 10 11 12 13 14

Kommentare zu diesen Handbüchern

Keine Kommentare

Wavetek 131A Bedienungsanleitung Seite 13

Kommentare zu diesen Handbüchern

Verwandte Produkte und Handbücher für Stromgeneratoren Wavetek 131A