Abstract
Long-term depression (LTD) reduces the functional strength of excitatory synapses through mechanisms that include the removal of AMPA glutamate receptors from the postsynaptic membrane. LTD induction is also known to result in structural changes at excitatory synapses, including the shrinkage of dendritic spines. Synaptic adhesion molecules are thought to contribute to the development, function and plasticity of neuronal synapses largely through their trans-synaptic adhesions. However, little is known about how synaptic adhesion molecules are altered during LTD. We report here that NGL-3 (netrin-G ligand-3), a postsynaptic adhesion molecule that trans-synaptically interacts with the LAR family of receptor tyrosine phosphatases and intracellularly with the postsynaptic scaffolding protein PSD-95, undergoes a proteolytic cleavage process. NGL-3 cleavage is induced by NMDA treatment in cultured neurons and low-frequency stimulation in brain slices and requires the activities of NMDA glutamate receptors, matrix metalloproteinases (MMPs) and presenilin/γ-secretase. These results suggest that NGL-3 is a novel substrate of MMPs and γ-secretase and that NGL-3 cleavage may regulate synaptic adhesion during LTD.
Highlights
Synaptic adhesion molecules play important roles in the regulation of synaptic development, function and plasticity [1,2,3,4,5,6,7,8,9,10,11,12,13,14]
We found that LTDinducing chemical and electrical stimuli caused proteolytic cleavage of NGL-3 in a manner requiring the activation of NMDA receptors, matrix metalloproteinases (MMPs) and g-secretase
Our data indicate that Long-term depression (LTD)-inducing stimuli promote proteolytic cleavage of NGL-3 in a manner that requires the activation of NMDA receptors, MMPs and presenilin/g-secretase
Summary
Synaptic adhesion molecules play important roles in the regulation of synaptic development, function and plasticity [1,2,3,4,5,6,7,8,9,10,11,12,13,14]. Many g-secretase substrates are synaptic surface proteins [83,84,85], including N-cadherin [86], ErbB4 [87,88], nectin-1a [89], syndecan-1/2/3 [85,90], GluR3 (GluA3) [91], ephrinB1/2 [92,93,94], EphA4/B2 [95,96], LAR [97], neurexin-1/3b [98,99] and neuroligin-1 [30,31] This suggests that g-secretase could act on these proteins to regulate synapse structure and function. We found that LTDinducing chemical and electrical stimuli caused proteolytic cleavage of NGL-3 in a manner requiring the activation of NMDA receptors, MMPs and g-secretase These results suggest that NGL-3 cleavage may regulate synaptic structure and function during LTD
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