PT  - JOURNAL ARTICLE
AU  - Rhalena A. Thomas
AU  - Julien Gibon
AU  - Carol X. Q. Chen
AU  - Sabrina Chierzi
AU  - Vincent G. Soubannier
AU  - Stephanie Baulac
AU  - Philippe Séguéla
AU  - Keith K. Murai
AU  - Philip A. Barker
TI  - The Nogo receptor ligand LGI1 regulates synapse number and synaptic activity in hippocampal and cortical neurons
AID  - 10.1523/ENEURO.0185-18.2018
DP  - 2018 Aug 27
TA  - eneuro
PG  - ENEURO.0185-18.2018
4099  - http://www.eneuro.org/content/early/2018/08/27/ENEURO.0185-18.2018.short
4100  - http://www.eneuro.org/content/early/2018/08/27/ENEURO.0185-18.2018.full
AB  - LGI1 is a secreted neuronal protein and a Nogo Receptor 1 (NgR1) ligand. Mutations in LGI1 in humans causes autosomal dominant lateral temporal lobe epilepsy and homozygous deletion of LGI1 in mice results in severe epileptic seizures that cause early postnatal death. NgR1 plays an important role in the development of central nervous system synapses and circuitry by limiting plasticity in the adult cortex via the activation of RhoA. These relationships and functions prompted us to examine the effect of LGI1 on synapse formation in vitro and in vivo. We report that application of LGI1 increases synaptic density in neuronal culture and that LGI1 null hippocampus has fewer dendritic mushroom spines than in wild-type littermates. Further, our electrophysiological investigations demonstrate that LGI1 null hippocampal neurons possess fewer and weaker synapses. RhoA activity is significantly increased in cortical cultures derived from LGI1 null mice and using a reconstituted system, we show directly that LGI1 antagonizes NgR1-TROY signaling. Our data suggests that LGI1 enhances synapse formation in cortical and hippocampal neurons by reducing NgR1 signaling.Significance statement Mutations in leucine-rich glioma inactivated protein 1 (LGI1) causes autosomal dominant lateral temporal lobe epilepsy in humans. In the present study we used a combination of cellular imaging, electrophysiology, protein analysis and cell biology assays to show that LGI1 promotes synapse formation and maturation. LGI1 deletion in mice results in fewer synapses and causes synaptic activity defects. Mechanistically, LGI1 regulates RhoA signaling through a receptor complex containing NgR1 and TROY. Our experiments provide evidence that NgR1 and LGI1 balance regulates RhoA activity during synapse formation and thus impacts on synapse maturation, number and activity.