RESEARCH HIGHLIGHTS

SYNAPTIC PLASTICITY 1 does the splits are postsynaptic adhesion Thus, NLGN1 cleavage can be release. In agreement with this, proteins that are essential for synaptic induced by neuronal activity or by blocking NLGN1 cleavage increased NLGN1 function, but little is known about binding with NRX1β, and this pro- presynaptic release probability. This cleavage can their precise role and regulation. vides a mechanism for the regulation suggests that NLGN1 cleavage acts Neuroligin 1 (NLGN1) is located post- of NLGN1 levels on the neuronal as a retrograde signal that modifies be induced synaptically at glutamatergic synapses, membrane. glutamate transmission. by neuronal where it binds to the presynaptic adhe- The two studies also provided Cleavage of NLGN1 also had activity or by sion protein 1β (NRX1β). in vivo evidence for activity-induced postsynaptic effects on dendritic binding with Now, two new papers shed light on the regulation of NLGN1 cleavage. The spines. Suzuki et al. overexpressed function and regulation of NLGN1. authors induced seizures in mice by different cleavage forms of the NRX1β Suzuki et al. detected several injecting them with pilocarpine and protein in rat dentate gyrus granule NLGN1 polypeptide fragments found that this increased levels of cells. Overexpression of full-length in immunoblots of rat brains and the NTF of NLGN1 in the forebrain NLGN1 increased spine density, as mouse primary cortical neuronal (Suzuki et al.) and in the hippocampus did overexpression of the membrane- cultures, which suggests that (Peixoto et al.). tethered carboxy-terminal fragment NLGN1 undergoes proteolytic pro- Peixoto et al. found that inhibi- of NLGN1, but not overexpression of cessing. Experiments with different tion of the matrix metalloproteinase the intracellular domain (that is, the enzyme inhibitors revealed that MMP9 prevented depolarization- product of cleavage by γ-secretase). the metalloproteinase ADAM10 induced NLGN1 cleavage in cortical In addition, Suzuki et al. found cleaves off NLGN1’s extracellular cultures. Moreover, MMP9-knockout that transfecting rat primary domain (that is, the soluble, amino- mice did not exhibit seizure-induced hippocampal with a terminal fragment (NTF)) and that and sensory experience-evoked mutant, cleavage-deficient form of γ-secretase cleaves off the intracel- NLGN1 cleavage, both of which were NLGN1 increased spine numbers. lular domain from the remaining robust in wild-type mice. Nevertheless, Together, these findings suggest that membrane-tethered fragment of basal NLGN1 NTFs could be detected acute activity-induced cleavage of the protein. in the brains of MMP9-knockout NLGN1 acts as a local homeostatic How is NLGN1 cleavage mice. It is possible that MMP9 is mechanism to regulate structural regulated? Peixoto et al. found that required for activity-induced cleavage and functional synaptic plasticity at depolarization (induced by treating of NLGN1, whereas basal cleavage is individual synapses. dissociated cortical cultures with mediated by ADAM10, as shown by Mutations in neurexin and KCl) rapidly reduced NLGN1 Suzuki et al. neuroligin have been associated levels at synapses and increased What is the functional conse- with . These two new studies levels of the NTF. Additional quence of activity-induced NLGN1 suggest that alterations in proteolytic treatment with an NMDA cleavage? Glutamate uncaging processing of NLGN1 could have a receptor antagonist prevented experiments by Peixoto et al. revealed role in the pathophysiology of this this effect, and both papers that NLGN1 cleavage occurs only in condition and possibly point to a showed that incubating cul- activated dendritic spines. The authors mechanism for the link between tures with NMDA increased found that acute NLGN1 cleavage epilepsy and autism. NTF levels. In addition, NTF destabilized NLGN1’s presynaptic Leonie Welberg

levels increased when Suzuki binding partner NRX1β. Furthermore, ORIGINAL RESEARCH PAPERS Suzuki, K. et al. et al. added soluble NRX1β electrophysiology experiments showed Activity-dependent proteolytic cleavage of neuroligin-1. 76, 410–422 (2012) | Peixoto, to the culture that NLGN1 cleavage reduced excita- R. T. et al. Transsynaptic signaling by activity- medium. tory neurotransmission by decreasing dependent cleavage of neuroligin-1. Neuron 76, the probability of neurotransmitter 396–409 (2012)

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NATURE REVIEWS | NEUROSCIENCE VOLUME 13 | DECEMBER 2012

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