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

Zhou, Yu; Lee, Sanghoon; Jin, Zhe; Wright, Moriah; Smith, Stephen; Anderson, Matthew P.

doi:10.1038/nm.2019

Cited by 170 publications

(212 citation statements)

References 43 publications

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“…However, inhibitory synaptic transmission is not affected in LGI1 mutant mice (7,13) and conditional LGI1 knock out in inhibitory parvalbumin interneurons does not confer an epileptic phenotype (8).…”

Section: Discussionmentioning

confidence: 99%

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LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

Seagar

Russier

Caillard

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

105

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Autosomal dominant epilepsy with auditory features results from mutations in leucine-rich glioma-inactivated 1 (LGI1), a soluble glycoprotein secreted by neurons. Animal models of LGI1 depletion display spontaneous seizures, however, the function of LGI1 and the mechanisms by which deficiency leads to epilepsy are unknown. We investigated the effects of pure recombinant LGI1 and genetic depletion on intrinsic excitability, in the absence of synaptic input, in hippocampal CA3 neurons, a classical focus for epileptogenesis. Our data indicate that LGI1 is expressed at the axonal initial segment and regulates action potential firing by setting the density of the axonal Kv1.1 channels that underlie dendrotoxin-sensitive D-type potassium current.LGI1 deficiency incurs a >50% down-regulation of the expression of Kv1.1 and Kv1.2 via a posttranscriptional mechanism, resulting in a reduction in the capacity of axonal D-type current to limit glutamate release, thus contributing to epileptogenesis.LGI1 | Kv1 channels | D-type current | intrinsic excitability | epilepsy

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Section: Discussionmentioning

confidence: 99%

“…Analysis of glutamatergic neurotransmission in hippocampal slices from Lgi1 −/− mice has yielded conflicting reports. Furthermore LGI1 has been implicated in neural development, and perturbed maturation may thus contribute to the epileptic phenotype (11)(12)(13).…”

mentioning

confidence: 99%

LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

Seagar

Russier

Caillard

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

105

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“…Another proteomic study identified the transmembrane proteins ADAM22 and ADAM23 as LGI1 receptors and suggested that LGI1 modulates synaptic function by stabilizing levels of cell surface AMPA receptors (Fukata et al, 2006). More recently, Zhou et al (2009) reported that LGI1 plays a role in the pruning and maturation of excitatory synapses in the hippocampus.…”

Section: Introductionmentioning

confidence: 99%

LGI1 Is a Nogo Receptor 1 Ligand that Antagonizes Myelin-Based Growth Inhibition

Thomas

Favell²,

Morante‐Redolat³

et al. 2010

J. Neurosci.

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Mutations in leucine-rich glioma inactivated (LGI1) are a genetic cause of autosomal dominant temporal lobe epilepsy with auditory features.LGI1 is a secreted protein that shares homology with members of the SLIT family, ligands that direct axonal repulsion and growth cone collapse, and we therefore considered the possibility that LGI1 may regulate neuronal process extension or growth cone collapse. Here we report that LGI1 does not affect growth directly but instead enhances neuronal growth on myelin-based inhibitory substrates and antagonizes myelin-induced growth cone collapse. We show that LGI1 mediates this effect by functioning as a specific Nogo receptor 1 (NgR1) ligand that antagonizes the action of myelin-based inhibitory cues. Finally, we demonstrate that NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22.

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“…In contrast to the roles of LGI1 in synaptic transmission, an alternative hypothesis that LGI1 regulates neuronal development was proposed by analyzing transgenic mice carrying the human ADPEAF mutation 835delC, which truncates the C-terminal EPTP domain of LGI1 (10). Thus, the physiological function of LGI1 in the brain remains controversial.…”

mentioning

confidence: 99%

Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

Fukata¹,

Lovero

Iwanaga³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

295

398

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Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1 −/− ) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3. Moreover, heterozygous mice for the LGI1 mutation (LGI1 +/− ) show lowered seizure thresholds. Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus. Thus, LGI1 may serve as a major determinant of brain excitation, and the LGI1 gene-targeted mouse provides a good model for human epilepsy.A ffecting 1-2% of the population, epilepsy is one of the most common neurological disorders. Epilepsy is characterized by recurrent unprovoked seizures and is caused by disturbances in the delicate balance between excitation and inhibition in neural circuits (1, 2). Recent human genetic studies have established the channelopathy concept for idiopathic (inherited) epilepsies: Many of the genes whose mutations cause human epilepsy encode ion channel subunits (1, 2). Examples include voltagegated ion channels (K + , Na + , Ca 2+ , and Cl -channels) and ligandgated ion channels (nicotinic acetylcholine and GABA A receptors), which regulate neuronal excitability.Leucine-rich glioma inactivated 1 (LGI1) is a unique human epilepsy-related gene in that it does not encode an ion channel subunit (3-5), but is a neuronal secreted protein (6). Mutations in LGI1 are linked to autosomal dominant partial epilepsy with auditory features (ADPEAF, also known as autosomal dominant lateral temporal lobe epilepsy [ADLTE]) (3-5), which is an inherited epileptic syndrome characterized by partial seizures with acoustic or visual hallucinations. So far, 25 LGI1 mutations have been described in familial ADPEAF patients and sporadic cases (7). Interestingly, at least six tested ADPEAF mutations all abolish LGI1 secretion (6,8).Recent proteomic analysis identified LGI1 as a subunit of presynaptic Kv 1 (shaker type)-voltage gated potassium channels (9). It was shown that LGI1 selectively prevents inactivation of the Kv 1 channel mediated by a cytoplasmic regulatory protein, Kvβ. Because LGI1 is a secreted protein, it remains unclear how LGI1 modulates a cytosolic potassium channel mechanism. LGI1 was also isolated from the brain as a component of a protein complex mediated by PSD-95, a representative postsynaptic scaffolding protein.LGI1 functions as a ligand for the epilepsy-related ADAM22 transmembrane protein, which is anchored by PS...

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

Cited by 170 publications

References 43 publications

LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

LGI1 Is a Nogo Receptor 1 Ligand that Antagonizes Myelin-Based Growth Inhibition

Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

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