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neurons varied among LGI1

/

mice, highlighting the importance

of seizure number and severity in neuronal degeneration.

Discussion

We report the electroclinical characterization of seizures in mice

deﬁcient for LGI1, the gene responsible for ADLTE. Two other

reports of LGI1 knockout mice, focusing mainly on in vitro dys-

function, have been published recently (Fukata et al., 2010; Yu

et al., 2010). Our results also demonstrate early onset spontan-

eous seizures with premature death in homozygous LGI1

/

mice

and an absence of spontaneous seizures in heterozygous LGI1

+/

mice. We have further characterized the phenotype of LGI1-deﬁ-

cient mice, showing (i) spontaneous epileptic activities with video–

EEG monitoring and providing details of seizure semiology;

(ii) seizure-induced hippocampal cell death and synaptic rearrange-

ment consistent with a temporal origin for ictal activity and

(iii) evidence that heterozygous LGI1

+/

mice have lowered

threshold to audiogenic seizures, reminiscent of human data for

seizures triggered by sound in some patients from ADLTE families.

Homozygous LGI1

/

mice: a model

for temporal lobe epilepsy?

Homozygous LGI1

/

mice were born in Mendelian ratios and

were undistinguishable from the LGI1

+/

and wild-type littermates

until age postnatal day 10. At that time, LGI1

/

mice began to

display spontaneous seizures that are lethal around postnatal

day 16. Video–EEG studies on LGI1

/

mice conﬁrmed that

acute behavioural manifestations were associated with epileptic

activities, both in the cortex and in the hippocampus. Since seiz-

ures in LGI1

/

animals were frequently initiated by behavioural

immobility, EEG records were crucial to deﬁne seizure occurrence

and duration. Initial seizures could be limited to motor arrest, fol-

lowed by grooming behaviours including forelimb licking (not

shown). Succeeding seizures tended to terminate with wild run-

ning and tonic–clonic movements. It seems likely that seizures

spread to motor areas only at seizure termination. In the absence

of EEG records, Yu et al. (2010) and Fukata et al. (2010), who

reported generalized myoclonic seizure and generalized seizures,

respectively, may have missed initial ictal symptoms.

Which brain regions underlie seizure initiation in LGI1

/

mice?

Our data suggest that spontaneous seizures may have a focal

onset reminiscent of complex partial seizures originating in the

human temporal lobe. The behaviour during seizures suggests a

sequential involvement of different brain areas as expected for

propagating epileptic discharges. Initial behaviour included motor

arrest and oroalimentary automatisms (forelimb licking, chewing).

Dystonic or tonic postures, frequently asymmetrical, tended to

involve the four limbs separately toward the end of seizures.

The organization of hippocampal EEG activity during seizures,

with initial low voltage fast activities followed by spike discharges

structured in amplitude and frequency, is similar to intracranial

EEG records of human temporal lobe seizures (Navarro et al.,

2002). Furthermore, ictal epileptic activities in the hippocampus

of LGI1

/

mice tended to precede cortical discharges, suggesting

that as in patients with ADLTE, seizures in mice originate focally in

Wild-type LGI1+/- LGI1-/-

P8P14

FED

Figure 7 Brain morphology of LGI1

/

mice. (A–C) at postnatal day 8 and (D–F) at postnatal day 14 (P14). Nissl-stained coronal

brain sections show similar brain morphology in (A and D) wild-type (n = 3), (B and E) LGI1

+/

(n = 3) and (C and F) LGI1

/

mice (n = 3).

Scale bars: 650 mm. Cx = cortex; Hipp = hippocampus; Th = thalamus; Ag = amygdala.

2758 | Brain 2010: 133; 2749–2762 E. Chabrol et al.

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