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Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy

Abstract

A subset of central glutamatergic synapses are coordinately pruned and matured by unresolved mechanisms during postnatal development. We report that the human epilepsy gene LGI1, encoding leucine-rich, glioma-inactivated protein-1 and mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTE), mediates this process in hippocampus. We created transgenic mice either expressing a truncated mutant LGI1 (835delC) found in ADLTE or overexpressing a wild-type LGI1. We discovered that the normal postnatal maturation of presynaptic and postsynaptic functions was arrested by the 835delC mutant LGI1, and contrastingly, was magnified by excess wild-type LGI1. Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission. Inhibitory transmission, by contrast, was unaffected. Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial γ-aminobutyric acidA (GABAA) receptor blockade. Thus, LGI1 represents a human gene mutated to promote epilepsy through impaired postnatal development of glutamatergic circuits (pages 1126–1127).

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Figure 1: LGI1 downregulates presynaptic release probability at hippocampal MPP-GC excitatory synapses via Kv1 channels during postnatal development.
Figure 2: LGI1 downregulates postsynaptic NR2B-dependent NMDA receptor currents during postnatal brain development.
Figure 3: mLGI1 blocks dendrite pruning during postnatal development and increases spine density.
Figure 4: mLGI1 increases glutamatergic synaptic transmission.
Figure 5: LGI1 trangenes fail to effect inhibitory synaptic transmission.
Figure 6: mLGI1 promotes epilepsy.

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Acknowledgements

We would like to thank C.B. Saper, J.S. Flier, D.K. Simon, G.D. Rosen, M.R. Kasten and M.W. Anderson for comments and suggestions, and G.D. Rosen for help on the Neurolucida system. This work was supported in part by the US National Institute of Neurological Disorders and Stroke R01 NS057444 (M.P.A.), US National Institute of Neurological Disorders and Stroke K02 NS054674-03 (M.P.A.), the Nancy Lurie Marks Family Foundation (M.P.A.), Autism Speaks/US National Alliance for Autism Research (M.P.A.) and Beth Israel Deaconess Medical Center.

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Contributions

Y.-D.Z. did electrophysiology, morphological reconstructions, in vivo kindling and EEG recording experiments. S.L. engineered the BAC constructs and characterized the transgenic mice. Z.J. and M.W. did immunoblotting and genotyping. S.E.P.S. did in situ hybridization experiments. M.P.A. and Y.-D.Z. designed the study, analyzed the data and wrote the paper.

Corresponding author

Correspondence to Matthew P Anderson.

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Supplementary Figures 1–12, Supplementary Table 1, Supplementary Note & Supplementary Methods (PDF 1550 kb)

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Zhou, YD., Lee, S., Jin, Z. et al. Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy. Nat Med 15, 1208–1214 (2009). https://doi.org/10.1038/nm.2019

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