Lgi2-deficient mice manifest epileptiform activity in the developing hippocampal network and ADHD-like behavioural comorbidity in adulthood.

Abstract

Genetic variants affecting brain development can lead to an increased risk of neurological disorders later in life. A protein-truncating variant in a gene for secreted neural protein LGI2 (Leucine-rich glioma-inactivated 2) is associated with remitting focal juvenile epilepsy and later behavioural disorders in Lagotto Romagnolo dogs. Yet, the developmental expression pattern of LGI2 in the brain and its association with neuronal network activities and behaviour have not been characterized. Here we show that Lgi2 gene expression is low in the neonatal mouse hippocampus but increases during juvenility (P14). Lgi2 is mainly expressed in GABAergic interneurons. Electrophysiological recordings using hippocampal slice cultures from LGI2 deficient mice revealed that Lgi2 ablation provokes ictal-like activity. We also found that adult LGI2-deficient mice have deficits in spatial reversal learning and impaired cognitive flexibility, thus paralleling Lagottos' behavioural ailments with ADHD-like symptoms. Therefore, our mouse model reveals functional defects in developing LGI2 deficient networks that associate with neurological disorders manifesting later in life.