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

Thomas, Rhalena A.; Favell, Kristy; Morante‐Redolat, José Manuel; Pool, Madeline; Kent, Christopher; Wright, Melissa; Daignault, Kathleen; Ferraro, Gino B.; Montcalm, Samuel; Durocher, Yves; Fournier, Alyson E.; Pérez‐Tur, Jordi; Barker, Philip A.

doi:10.1523/jneurosci.5147-09.2010

Cited by 73 publications

(83 citation statements)

References 32 publications

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“…LGI1 is a soluble protein that interacts with membranes by binding to its receptors ADAM22, ADAM23 (22), and NogoR (11). Previous investigation underlined a postsynaptic localization for ADAM22 (22), difficult to reconcile with the view that LGI1 sets the density of axonal Kv1.1 channels (25).…”

Section: Exogenousmentioning

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: Exogenousmentioning

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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“…Slice cultures were prepared from P6-P8 animals, before seizure onset in LGI1 −/− mice, and recordings were made at day in vitro (DIV) 8 (Fig. 1A), a time at which LGI1 and other major synaptic proteins are robustly expressed (18)(19)(20).…”

Section: Significancementioning

confidence: 99%

“…Notably, LGI1 and ADAM22 are found in complex with the mature MAGUKs, in vivo (18,19), and their expression levels follow a similar timeline (17,18,20). However, little is known about the neuronal function of ADAM11, ADAM22, and ADAM23, and it is not clear which mediates the function of LGI1 at the synapse.…”

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confidence: 99%

The LGI1–ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function

Lovero

Fukata

Granger

et al. 2015

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

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Synapse development is coordinated by a number of transmembrane and secreted proteins that come together to form synaptic organizing complexes. Whereas a variety of synaptogenic proteins have been characterized, much less is understood about the molecular networks that support the maintenance and functional maturation of nascent synapses. Here, we demonstrate that leucine-rich, gliomainactivated protein 1 (LGI1), a secreted protein previously shown to modulate synaptic AMPA receptors, is a paracrine signal released from pre-and postsynaptic neurons that acts specifically through a disintegrin and metalloproteinase protein 22 (ADAM22) to set postsynaptic strength. We go on to describe a novel role for ADAM22 in maintaining excitatory synapses through PSD-95/Dlg1/zo-1 (PDZ) domain interactions. Finally, we show that in the absence of LGI1, the mature synapse scaffolding protein PSD-95, but not the immature synapse scaffolding protein SAP102, is unable to modulate synaptic transmission. These results indicate that LGI1 and ADAM22 form an essential synaptic organizing complex that coordinates the maturation of excitatory synapses by regulating the functional incorporation of PSD-95.P roper development of synapses involves recruitment of proteins that establish presynaptic release sites and postsynaptic densities (PSDs), and later coordinate maturation, maintenance, and plasticity of the synapse. In the last decade, a number of transmembrane synaptic adhesion proteins and secreted proteins that initiate and modulate excitatory synapses-termed synaptic organizing proteins-have been identified (1, 2). Whereas the synaptogenic properties of many synaptic organizing proteins have been described in detail (2-11), much less is known about how synaptic organizing proteins regulate synapse maintenance and maturation (1).A key component to the functional maturation of excitatory synapses is the recruitment of AMPA-type glutamate receptors (AMPARs) to the PSD, which is coordinated by PSD-95/Dlg1/ zo-1 (PDZ) domain-containing scaffolding proteins (12). Specifically, one family of PDZ proteins, the membrane-associated guanylyl kinases (MAGUKs), is known to determine basal synaptic AMPAR content (13-16). Like synaptic AMPAR content, the expression of different MAGUKs is developmentally regulated; whereas synapse-associated protein 102 (SAP102) is expressed in the early postnatal period and is critical to the function of immature synapses, postsynaptic density proteins 93 and 95 (PSD-93 and PSD-95) are first expressed around postnatal day 10 (P10) and are required for proper function of mature synapses (14, 17). Mice lacking PSD-93 and PSD-95 have synapses with significantly reduced AMPAR content (14), indicating the shift in MAGUK expression is critical to synapse maturation. However, what guides the incorporation of PSD-93 and PSD-95 into developing synapses remains unknown.We recently identified an instructive role for leucine-rich, gliomainactivated protein 1 (LGI1) in regulating synaptic AMPAR content-application of LGI1 incr...

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“…NgR1 is a GPI-anchored protein expressed in neurons of the adult CNS [9,10]. NgR1 and its analogue NgR3 are receptors for chondroitin sulfate proteogylcans (CSPGs) [11] also, and NgR1 has been demonstrated to interact with additional functional proteins, including olfactomedin 1 [12] and leucine-rich glioma inactivated (LGI1) [13]. For signal transduction NgR1 interacts with co-receptors p75 or TROY, and Lingo-1 [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Blocking Nogo Receptor 1 Promotes Functional Regeneration after Spinal Cord Injury

A¹,

AH²

2013

J Neurol Disord

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

Cited by 73 publications

References 32 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

The LGI1–ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function

Blocking Nogo Receptor 1 Promotes Functional Regeneration after Spinal Cord Injury

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