Electroclinical characterization of epileptic seizures in leucine-rich, glioma-inactivated 1-deficient mice

Abstract

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 spontaneous 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+/− littermates 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.

The LGI1–ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function

“…Consistent with these data, LGI1 is found bound to ADAM22 most often in vivo (19). Additionally, mice lacking ADAM11 do not exhibit a lethal epileptic phenotype (38), unlike LGI1-lacking or ADAM22-lacking mice (19,21,22,39), suggesting that ADAM11 may not share a functional role with these proteins. In the future, it will be of interest to determine if ADAM11 and ADAM23 impact synaptic transmission as well and the nature of their interaction with LGI1.…”

“…However, mice lacking LGI1 exhibit a lethal epilepsy phenotype, with seizures starting in the second postnatal week that are invariably fatal by postnatal week 3 (19,21,22). Thus, we…”

“…turned to hippocampal slice culture, a system in which we are able to both investigate single-cell genetic manipulations and also bypass the potential confounding effects of repeated seizures in vivo (21,23). Slice cultures were prepared from P6-P8 animals, before seizure onset in LGI1 −/− mice, and recordings were made at day in vitro (DIV) 8 (Fig.…”

The expanding spectrum of clinically-distinctive, immunotherapy-responsive autoimmune encephalopathies

“…Interestingly, further evidence for the disease relevance of these proteins come from known genetic variations. Human LGI1-mutations produce a lateral temporal lobe epilepsy syndrome 17 and mice lacking LGI1 show a variety of motor semiologies 18 . Humans with CASPR2 mutations present autism, seizures, and peripheral neuropathy 19 .…”

LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

“…Most ADEAF mutations impair secretion of the protein (3,4). Animal models of LGI1 depletion, including Lgi1 −/− mice (5)(6)(7)(8), mutant rats (9), and knockdown in zebrafish (10), all display spontaneous seizures. However, the mechanisms by which LGI1 deficiency leads to epilepsy are unknown.…”