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

Abstract

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...

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

“…In contrast, in acute hippocampal slices of P14/15 mice lacking Lgi1 , decreased mEPSC amplitudes and a reduced AMPA/NMDA ratio indicated postsynaptic effects . Similar results were observed in CA1 or dentate gyrus granule cells from cultured hippocampal slices prepared from Lgi1 null mice at P6–8 before seizure onset . The reason for these discrepancies is not known, but additional experiments indicated that LGI1 promotes postsynaptic maturation through ADAM22 and PSD‐95 .…”

“…Antibody‐mediated interference with the LGI1–ADAM22–PSD‐95 link is expected to alter the composition of the postsynaptic density as well. This might result in deficient AMPAR recruitment and underlie cognitive deficits in LGI1 encephalitis. It is possible that the inhibitory effects of LGI1 antibodies are limited by the accessibility of mature synaptic structures and are detected only after long exposition times.…”

“…19 Similar results were observed in CA1 or dentate gyrus granule cells from cultured hippocampal slices prepared from Lgi1 null mice at P6-8 before seizure onset. 16 The reason for these discrepancies is not known, but additional experiments indicated that LGI1 promotes postsynaptic maturation through ADAM22 and PSD-95. 16 Antibody-mediated interference with the LGI1-ADAM22-PSD-95 link is expected to alter the composition of the postsynaptic density as well.…”

Persistent sodium current blockers can suppress seizures caused by loss of low‐threshold D‐type potassium currents: Predictions from an in silico study of Kv1 channel disorders

“…Associated epilepsy phenotypes can be refractory to existing antiepileptic medications, often with devastating sequelae. LGI1 encodes a protein that regulates the expression and function of K v 1 channels and AMPA receptors . In LGI1 knockout models, the expression of K v 1.1 and K v 1.2 channels is reduced by more than 50% .…”

Emerging psychiatric syndromes associated with antivoltage-gated potassium channel complex antibodies

“…The underlying mechanisms of disease might include that LGI1 can influence synaptic transmission in the hippocampus by modulating the ratio of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) versus NMDA receptors19 and by supporting the maturation of NMDA receptors in the hippocampus 20. Moreover, experiments with LGI1 antibody-containing human serum could enhance the excitability at hippocampal synapses in slice experiments,21 which is believed to facilitate the process of memory encryption,22 thus supporting that VGKCC antibodies are directly pathogenic.…”