Deciphering LGI1-related epilepsy using conditional knockouts – LGI1 KO

In order to reproduce the genetic alteration found in patients, we have generated knockout mice, in which Lgi1 is deleted. Thanks to the use of several transgenic mice strains, we will be able to delete Lgi1 in restricted brain regions, specific cell-type as well as at a precise period of time. These different models will allow us to test multiple hypotheses on the pathway involving Lgi1 and it’s role in the modulation of the circuit excitability in the immature and mature brain.

Selective deletion of Lgi1 in embryonic excitatory neurons caused severe early-onset seizures, whereas deletion in adult excitatory neurons caused a milder phenotype, with infrequent and late-onset seizures. In contrast, neither spontaneous seizures nor increased neurons. Together, these data showed that deletion of Lgi1 in excitatory neurons suffices to generate spontaneous seizures in mice, and that Lgi1 displays an essential role in brain during the whole life. We suggest that Lgi1 secreted from excitatory neurons, but not parvalbumin inhibitory neurons, makes a major contribution to the pathogenesis of Lgi1-related epilepsies. Our data further indicates Lgi1 is required from embryogenesis to adulthood to achieve proper circuit functioning.

We have developed several Lgi1 knockout mice, which are pertinent models for spontaneous non-lesional epilepsy. These animal models will be useful to test novel antiepileptic drugs with new mechanism of action, and will promote interaction with pharmaceutical industry.

1. Boillot M, Huneau C, Marsan E, Lehongre K, Navarro V, Ishida S, Dufresnois B, Ozkaynak E, Garrigue J, Miles R, Martin B, Leguern E, Anderson M and Baulac S (2014). Glutamatergic neuron-targeted loss of Lgi1-epilepsy gene results in seizures. Brain, Nov;137(Pt 11):2984-96.
2. Boillot M and Baulac S (2015). Models of genetic focal epilepsies: from genes to seizures. Journal of Neuroscience Methods. In press
3. Boillot M. et al. en preparation. Lgi1 modulates glutamatergic synaptic efficacy and neuronal excitability.

Up until recently, nearly all mutated genes linked to idiopathic epilepsies encoded components of ion channels or neurotransmitter receptors. LGI1 (leucine-rich, glioma-inactivated 1) is one of the exceptions. LGI1 encodes a protein secreted by neurons with no homology with known ion channel genes.
Mutations of the LGI1 gene underlie a focal idiopathic inherited epilepsy disorder named autosomal dominant lateral temporal epilepsy (ADLTE). ADLTE is characterized by focal seizures of adolescence onset. Specific features of the syndrome are the presence of auditory auras or seizures triggered by sound.

Since LGI1 mutations are predicted to cause haploinsufficiency in epileptic patients, we have attempted to model the human genetic condition by disrupting LGI1 gene. We have shown that germline knockout (KO) of LGI1 causes recurrent spontaneous early onset epileptic seizures associated with premature death of LGI1-/- mice.

In this present project, we will use brain region-, cell-type-, and developmentally-restricted ablation of LGI1 using the LGI1-floxed mice that we have already generated. We expect that this work should not only help to resolve the pathophysiological mechanisms of LGI1-related epilepsy but also the normal function of this newly-identified secreted neuronal protein.