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are typical for patients with temporal lobe epilepsies as well as

numerous animal models of hippocampal seizures (Dudek and

Sutula, 2007). No such morphological modiﬁcations were present

in LGI1

/

pups at postnatal day 8 before seizure onset, or in

LGI1

+/

and wild-type animals. Taken together, evidence for ana-

tomical changes in the hippocampus, for a hippocampal origin of

ictal activity and for strong expression of LGI1 in the dentate gyrus

and CA3 region (Herranz-Perez et al., 2010) support a localization

of LGI1-related epileptic activity to this region.

Heterozygous LGI1

+/

mice: a model

for ADLTE?

Since human LGI1 mutations are linked to ADLTE, an autosomal

dominant trait, we searched for epileptic behaviour in heterozy-

gous LGI1

+/

mice. These animals showed no evidence of spon-

taneous behavioural epileptic seizures at any age up to 15 months.

We cannot completely exclude rare seizures, but the absence of

pathological changes in hippocampal anatomy suggests that het-

erozygous mice did not experience recurrent subclinical seizures.

However, adult LGI1

+/

mice were more susceptible to

sound-induced seizures than wild-type littermates, as are some

patients with ADLTE. Audiogenic seizures possessed a comparable

age dependence and similar violent behavioural manifestations,

including wild running and clonic or tonic activities, to those

induced in wild-type mice (Seyfried et al., 1999). This susceptibility

is striking, since the C57BL/6 mouse strain is normally resistant to

audiogenic seizures. Our LGI1-deﬁcient mice were derived from

75% C57BL/6 and 25% 129S2Sv/pas hybrid background, sug-

gesting that LGI1 deﬁciency underlies their susceptibility to audio-

genic seizures. Interestingly, both LGI1 and the mass1 gene,

mutated in the Frings mouse model of audiogenic epilepsy

(Skradski et al., 2001), share structural homology, including

epilepsy-associated repeats (Scheel et al., 2002).

Altogether, our ﬁndings highlight a gene dosage relation be-

tween LGI1 and epileptic syndromes. Lack of one LGI1 copy con-

fers an enhanced susceptibility to auditory-evoked seizures, as in

some patients with ADLTE, while early onset spontaneous seizures

occur in mice lacking two copies. These observations indicate that

LGI1 knockout mice could provide two distinct animal models for

epilepsy: heterozygous mice recapitulate the genetic cause and

mimic the human condition with an auditory epileptogenic trigger,

while homozygous mice are interesting due to an early onset of

spontaneous seizures with a probable origin in the temporal lobe

structures. In particular, this model may be useful in studies on the

temporal development of seizures and the spatial recruitment of

distant brain structures as well as the electrical characterization of

the transition to seizure or ictogenesis. Our results conﬁrm genetic

evidence that LGI1 haploinsufﬁciency can lead to seizures. The

LGI1 knockout mouse thus provides a novel non-lesional epileptic

mouse model that may open new therapeutical avenues for

CBA

FED

IHG

Wild-type LGI1+/- LGI1-/-

Figure 9 Absence of morphological alterations in LGI1

/

mice aged postnatal day 8 before seizures. (A–C) Nissl-staining of dentate

gyrus. (A) Wild-type (n = 3), (B) LGI1

+/

(n = 3) and (C) LGI1

/

(n = 3) mice. (D–F) Glial ﬁbrillary acidic protein immunostaining with

cresyl violet counterstaining of the hippocampus of (D) wild-type (n = 3), (E) LGI1

+/

(n = 3) and (F) LGI1

/

(n = 3) mice. (G–I) Zinc

transporter 3 (ZnT3) immunostaining with cresyl violet counterstaining of the hippocampus of (G) wild-type (n = 3), (H) LGI1

+/

(n =3)

and (I) LGI1

/

(n = 3) mice. Scale bars: 300 m m(A–B); 40 mm(D–I).

2760 | Brain 2010: 133; 2749–2762 E. Chabrol et al.

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