Activity-Dependent Proteolytic Cleavage of Neuroligin-1

Department of Neuropathology and Neuroscience, The University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo 113-0033, Japan.
Neuron (Impact Factor: 15.05). 10/2012; 76(2):410-22. DOI: 10.1016/j.neuron.2012.10.003
Source: PubMed


Neuroligin (NLG), a postsynaptic adhesion molecule, is involved in the formation of synapses by binding to a cognate presynaptic ligand, neurexin. Here we report that neuroligin-1 (NLG1) undergoes ectodomain shedding at the juxtamembrane stalk region to generate a secreted form of NLG1 and a membrane-tethered C-terminal fragment (CTF) in adult rat brains in vivo as well as in neuronal cultures. Pharmacological and genetic studies identified ADAM10 as the major protease responsible for NLG1 shedding, the latter being augmented by synaptic NMDA receptor activation or interaction with soluble neurexin ligands. NLG1-CTF was subsequently cleaved by presenilin/γ-secretase. Secretion of soluble NLG1 was significantly upregulated under a prolonged epileptic seizure condition, and inhibition of NLG1 shedding led to an increase in numbers of dendritic spines in neuronal cultures. Collectively, neuronal activity-dependent proteolytic processing of NLG1 may negatively regulate the remodeling of spines at excitatory synapses.

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    • "Similarly, it has recently been shown that NLG-1 undergoes ectodomain shedding by ADAM10 (Suzuki et al., 2012). Interestingly , neuronal activity increased shedding of NLG-1 and thus might negatively regulate remodeling of spines (Suzuki et al., 2012). In line with this, also Calsyntenin 3 is subject to ectodomain shedding (Araki et al., 2004), whereas membrane anchored Calsyntenin 3 displays a higher synaptogenic activity than its secreted form (Pettem et al., 2013). "
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    • "Our results are reminiscent of the recently reported activity-dependent cleavage of neuroligin-1 mediated by MMP-9/ADAM-10 and γ-secretase [30,31]. Neurexin-1β and neurexin-3β, which interact with neuroligins, have also been shown to be substrates of γ-secretase [98,99]. "
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    • "(B) Activity-dependent redistribution of adhesion molecules over the axonal membrane can facilitate synapse formation (Fu and Huang, 2010). (C) Activity-dependent cleavage of synaptic adhesion molecules could induce synapse disassembly or plasticity (Matsumoto-Miyai et al., 2009; O'Connor et al., 2009; Peixoto et al., 2012; Suzuki et al., 2012). (D) Activity-dependent changes in binding properties of adhesion molecules (Kim et al., 2011a,b) could affect synaptic properties. "
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