Mutations of the
leucine-rich
glioma-inactivated 1 (LGI1) gene cause an
autosomal dominant partial epilepsy with auditory features also known as
autosomal-dominant lateral temporal lobe epilepsy. LGI1 is also the main
antigen present in sera and cerebrospinal fluids of patients with
limbic encephalitis and
seizures, highlighting its importance in a spectrum of epileptic disorders. LGI1 encodes a neuronal secreted
protein, whose brain function is still poorly understood. Here, we generated, by ENU (
N-ethyl-N-nitrosourea) mutagenesis, Lgi1-mutant rats carrying a missense mutation (L385R). We found that the L385R mutation prevents the secretion of Lgi1
protein by COS7 transfected cells. However, the L385R-Lgi1
protein was found at low levels in the brains and cultured neurons of Lgi1-mutant rats, suggesting that
mutant protein may be destabilized in vivo. Studies on the behavioral phenotype and intracranial electroencephalographic signals from Lgi1-mutant rats recalled several features of the human
genetic disorder. We show that homozygous Lgi1-mutant rats (Lgi1(L385R/L385R)) generated early-onset spontaneous epileptic
seizures from P10 and died prematurely. Heterozygous Lgi1-mutant rats (Lgi1(+/L385R)) were more susceptible to sound-induced,
generalized tonic-clonic seizures than control rats. Audiogenic
seizures were suppressed by
antiepileptic drugs such as
carbamazepine,
phenytoin and
levetiracetam, which are commonly used to treat
partial seizures, but not by the prototypic
absence seizure drug,
ethosuximide. Our findings provide the first rat model with a missense mutation in Lgi1 gene, an original model complementary to knockout mice. This study revealed that LGI1 disease-causing missense mutations might cause a depletion of the
protein in neurons, and not only a failure of Lgi1 secretion.