Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
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 gamma-aminobutyric acid(A) (GABA(A)) receptor blockade. Thus, LGI1 represents a human gene mutated to promote epilepsy through impaired postnatal development of glutamatergic circuits.
Zhou
Yu-Dong
YD
Departments of Neurology and Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Lee
Sanghoon
S
Jin
Zhe
Z
Wright
Moriah
M
Smith
Stephen E P
SE
Anderson
Matthew P
MP
D000818:Animals; D004833:Epilepsy, Temporal Lobe / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D005799:Genes, Dominant; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D018080:Receptors, GABA-B / Q000235:genetics; D013569:Synapses / Q000235:genetics*; D019076:Transgenes
D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; C492120:Lgi1 protein, mouse; D011506:Proteins; D018080:Receptors, GABA-B
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