Autoantibodies to Epilepsy-Related LGI1 in Limbic Encephalitis Neutralize LGI1-ADAM22 Interaction and Reduce Synaptic AMPA Receptors

Ohkawa, Taka-aki; Fukata, Yuko; Yamasaki, Miwako; Miyazaki, Toru; Yokoi, Norihiko; Takashima, Hiroshi; Watanabe, Masahiko; Watanabe, Osamu; Fukata, Masaki

doi:10.1523/jneurosci.3506-13.2013

Cited by 313 publications

(295 citation statements)

References 46 publications

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“…Our results support and extend reports of enhanced excitatory transmission in Lgi1 −/− mice (7,21). It is possible that conflicting evidence, suggesting reduced AMPA receptor function in Lgi1 −/− mice (6,22,23), may be the consequence of homeostatic synaptic responses to increased excitatory transmission.…”

Section: Discussionsupporting

confidence: 89%

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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: Discussionsupporting

confidence: 89%

“…Analysis of glutamatergic neurotransmission in hippocampal slices from Lgi1 −/− mice has yielded conflicting evidence, as both enhanced excitatory transmission (7,21) and reduced AMPA receptor function (6,22,23) have been reported.…”

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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“…Patients with limbic encephalitis (LE) develop adult-onset epilepsy and neuropsychiatric symptoms, such as memory deficits and psychosis (43). Research into the mechanism of action of autoantibodies has shown that antibodies isolated from LE patients target LGI1, disrupting the LGI1-ADAM22 interaction and reducing synaptic AMPARs (44). So, whereas it may be that the epilepsy phenotype related to mutations in LGI1 is a result of improper neurite development, it is certain that disruption of the LGI1-ADAM complex in the mature adult brain can also produce disease, indicating a critical function for this complex in synaptic maintenance as well as development.…”

Section: Discussionmentioning

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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“…LGI1 is thought to interact presynaptically with the VGKC complex and postsynaptically with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), and the antibodies also reduce AMPAR expression in vitro [55]. Other forms of limbic encephalitis in adults with antibodies to the VGKC complex protein contactin-associated protein 2, γ-aminobutyric acid (b) receptor , or AMPAR may not be clinically distinguishable from this form of limbic encephalitis at presentation but can now be identified by specific antibody tests and are associated with tumors.…”

Section: Antibodies To Identified Cns Proteinsmentioning

confidence: 99%

Neuroinflammation: Ways in Which the Immune System Affects the Brain

et al. 2015

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Neuroinflammation is the response of the central nervous system (CNS) to disturbed homeostasis and typifies all neurological diseases. The main reactive components of the CNS include microglial cells and infiltrating myeloid cells, astrocytes, oligodendrocytes, and the blood-brain b a r r i e r , c y t o k i n e s , a n d c y t o k i n e s i g n a l i n g . Neuroinflammatory responses may be helpful or harmful, as mechanisms associated with neuroinflammation are involved in normal brain development, as well as in neuropathological processes. This review examines the roles of various cell types that contribute to the immune dysregulation associated with neuroinflammation. Microglia enter the CNS very early in embryonic development and, as such, play an essential role in both the healthy and diseased brain. B-cell diversity contributes to CNS disease through both antibody-dependent and antibody-independent mechanisms. The influences of these B-cell mechanisms on other cell types, including myeloid cells and T cells, are reviewed in relationship to antibody-mediated CNS disorders, paraneoplastic neurological diseases, and multiple sclerosis. New insights into neuroinflammation offer exciting opportunities to investigate potential therapeutic targets for debilitating CNS diseases.

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Autoantibodies to Epilepsy-Related LGI1 in Limbic Encephalitis Neutralize LGI1-ADAM22 Interaction and Reduce Synaptic AMPA Receptors

Cited by 313 publications

References 46 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

Neuroinflammation: Ways in Which the Immune System Affects the Brain

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