Activity-Dependent Proteolytic Cleavage of Neuroligin-1 (original) (raw)
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Neuroligin-1 Loss Is Associated with Reduced Tenacity of Excitatory Synapses
Neuroligins (Nlgns) are postsynaptic, integral membrane cell adhesion molecules that play important roles in the formation, validation, and maturation of synapses in the mammalian central nervous system. Given their prominent roles in the life cycle of synapses, it might be expected that the loss of neuroligin family members would affect the stability of synaptic organization, and ultimately, affect the tenacity and persistence of individual synaptic junctions. Here we examined whether and to what extent the loss of Nlgn-1 affects the dynamics of several key synaptic molecules and the constancy of their contents at individual synapses over time. Fluorescently tagged versions of the postsynaptic scaffold molecule PSD-95, the AMPA-type glutamate receptor subunit GluA2 and the presynaptic vesicle molecule SV2A were expressed in primary cortical cultures from Nlgn-1 KO mice and wild-type (WT) littermates, and live imaging was used to follow the constancy of their contents at individual synapses over periods of 8-12 hours. We found that the loss of Nlgn-1 was associated with larger fluctuations in the synaptic contents of these molecules and a poorer preservation of their contents at individual synapses. Furthermore, rates of synaptic turnover were somewhat greater in neurons from Nlgn-1 knockout mice. Finally, the increased GluA2 redistribution rates observed in neurons from Nlgn-1 knockout mice were negated by suppressing spontaneous network activity. These findings suggest that the loss of Nlgn-1 is associated with some use-dependent destabilization of excitatory synapse organization, and indicate that in the absence of Nlgn-1, the tenacity of excitatory synapses might be somewhat impaired.
Neuroligin-1 mediates presynaptic maturation through brain-derived neurotrophic factor signaling
BMC Biology, 2021
Background Maturation is a process that allows synapses to acquire full functionality, optimizing their activity to diverse neural circuits, and defects in synaptic maturation may contribute to neurodevelopmental disorders. Neuroligin-1 (NL1) is a postsynaptic cell adhesion molecule essential for synapse maturation, a role typically attributed to binding to pre-synaptic ligands, the neurexins. However, the pathways underlying the action of NL1 in synaptic maturation are incompletely understood, and some of its previously observed effects seem reminiscent of those described for the neurotrophin brain-derived neurotrophic factor (BDNF). Here, we show that maturational increases in active zone stability and synaptic vesicle recycling rely on the joint action of NL1 and brain-derived neurotrophic factor (BDNF). Results Applying BDNF to hippocampal neurons in primary cultures or organotypical slice cultures mimicked the effects of overexpressing NL1 on both structural and functional matu...
Silencing of Neuroligin Function by Postsynaptic Neurexins
Journal of Neuroscience, 2007
The formation of neuronal circuits during development involves a combination of synapse stabilization and elimination events. Synaptic adhesion molecules are thought to play an important role in synaptogenesis, and several trans-synaptic adhesion systems that promote the formation and maturation of synapses have been identified. The neuroligin-neurexin complex is a heterophilic adhesion system that promotes assembly and maturation of synapses through bidirectional signaling. In this protein complex, postsynaptic neuroligins are thought to interact trans-synaptically with presynaptic neurexins. However, the subcellular localization of neurexins has not been determined. Using immunoelectron microscopy, we found that endogenous neurexins and epitope-tagged neurexin-1 are localized to axons and presynaptic terminals in vivo. Unexpectedly, neurexins are also abundant in the postsynaptic density. cis-expression of neurexin-1 with neuroligin-1 inhibits trans-binding to recombinant neurexins, blocks the synaptogenic activity of neuroligin-1, and reduces the density of presynaptic terminals in cultured hippocampal neurons. Our results demonstrate that the function of neurexin proteins is more diverse than previously anticipated and suggest that postsynaptic cis-interactions might provide a novel mechanism for silencing the activity of a synaptic adhesion complex.
Proceedings of the National Academy of Sciences, 2011
Synaptic cell adhesion molecules, including the neurexin ligands, neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs), are thought to organize synapse assembly and specify synapse function. To test the synaptic role of these molecules in vivo, we performed lentivirally mediated knockdown of NL3, LRRTM1, and LRRTM2 in CA1 pyramidal cells of WT and NL1 KO mice at postnatal day (P)0 (when synapses are forming) and P21 (when synapses are largely mature). P0 knockdown of NL3 in WT or NL1 KO neurons did not affect excitatory synaptic transmission, whereas P0 knockdown of LRRTM1 and LRRTM2 selectively reduced AMPA receptor-mediated synaptic currents. P0 triple knockdown of NL3 and both LRRTMs in NL1 KO mice yielded greater reductions in AMPA and NMDA receptor-mediated currents, suggesting functional redundancy between NLs and LRRTMs during early synapse development. In contrast, P21 knockdown of LRRTMs did not alter excitatory transmission, whereas NL manipulations supported a role for NL1 in maintaining NMDA receptor-mediated transmission. These results show that neurexin ligands in vivo form a dynamic synaptic cell adhesion network, with compensation between NLs and LRRTMs during early synapse development and functional divergence upon synapse maturation. hippocampus | neuropsychiatric disorders T he enormous processing power of the mammalian brain is the result of a vast network of precise synaptic connections, where functionally diverse presynaptic neurons establish synapses with specific properties onto select populations of postsynaptic cells. Neuroligins (NLs) and neurexins (NRXs) are a prototypical transsynaptic adhesion pair (1, 2) that is ideally situated to play important roles in such synaptic processes. Interactions between the four NLs (NL1-4) and the three NRXs are highly regulated at the level of alternative mRNA splicing, generating an intricate code that regulates both the affinity of interactions and the consequences on synapse specification (3, 4). Given the complexity of NL-NRX interactions, it was surprising to find that leucine-rich repeat transmembrane proteins (LRRTMs) are also high-affinity receptors for NRXs and share many of the binding characteristics of NLs .
Neuroligin-1 performs neurexin-dependent and neurexin-independent functions in synapse validation
Embo Journal, 2009
Postsynaptic neuroligins are thought to perform essential functions in synapse validation and synaptic transmission by binding to, and dimerizing, presynaptic aand b-neurexins. To test this hypothesis, we examined the functional effects of neuroligin-1 mutations that impair only a-neurexin binding, block both aand b-neurexin binding, or abolish neuroligin-1 dimerization. Abolishing a-neurexin binding abrogated neuroligin-induced generation of neuronal synapses onto transfected non-neuronal cells in the so-called artificial synapse-formation assay, even though b-neurexin binding was retained. Thus, in this assay, neuroligin-1 induces apparent synapse formation by binding to presynaptic a-neurexins. In transfected neurons, however, neither anor b-neurexin binding was essential for the ability of postsynaptic neuroligin-1 to dramatically increase synapse density, suggesting a neurexin-independent mechanism of synapse formation. Moreover, neuroligin-1 dimerization was not required for either the nonneuronal or the neuronal synapse-formation assay. Nevertheless, both a-neurexin binding and neuroligin-1 dimerization were essential for the increase in apparent synapse size that is induced by neuroligin-1 in transfected neurons. Thus, neuroligin-1 performs diverse synaptic functions by mechanisms that include as essential components of a-neurexin binding and neuroligin dimerization, but extend beyond these activities. EMBO THE EMBO JOURNAL THE EMBO JOURNAL Neurexin-dependent functions of neuroligin-1 J Ko et al
Neuroligins mediate excitatory and inhibitory synapse formation
Journal of Biological …, 2005
The balance between excitatory and inhibitory synapses is a tightly regulated process that requires differential recruitment of proteins that dictate the specificity of newly formed contacts. However, factors that control this process remain unidentified. Here we show that members of the neuroligin (NLG) family, including NLG1, NLG2, and NLG3, drive the formation of both excitatory and inhibitory presynaptic contacts. The enrichment of endogenous NLG1 at excitatory contacts and NLG2 at inhibitory synapses supports an important in vivo role for these proteins in the development of both types of contacts. Immunocytochemical and electrophysiological analysis showed that the effects on excitatory and inhibitory synapses can be blocked by treatment with a fusion protein containing the extracellular domain of neurexin-1. We also found that overexpression of PSD-95, a postsynaptic binding partner of NLGs, resulted in a shift in the distribution of NLG2 from inhibitory to excitatory synapses. These findings reveal a critical role for NLGs and their synaptic partners in controlling the number of inhibitory and excitatory synapses. Furthermore, relative levels of PSD-95 alter the ratio of excitatory to inhibitory synaptic contacts by sequestering members of the NLG family to excitatory synapses.
Alternative Splicing of Neuroligin Regulates the Rate of Presynaptic Differentiation
Journal of Neuroscience, 2010
Neuroligins (NLGs) and Neurexins (NRXs) are important adhesion molecules that promote synapse formation. Multiple splice variants of NLG and NRX exist, but their specific functions are unclear. Here we report that a surrogate postsynaptic cell expressing full-length NLG-1 triggers slow presynaptic differentiation in a contacting axon. In contrast, a version of NLG-1, which lacks insert B (NLG-1⌬B), induces rapid presynaptic differentiation, reaching the rate seen at native neuronal synapses. We show that this acceleration is attributed to the removal of the N-linked glycosylation site within insert B. NLG-1⌬B also increases synaptic density at neuro-neuronal synapses more than does full-length NLG-1. Other postsynaptic adhesion proteins, such as N-cadherin, EphB2, and SynCAM-1, alone or in combination with full-length NLG-1, do not trigger fast differentiation, suggesting that rapid presynaptic differentiation depends on a unique interaction of NLG-1⌬B with axonal proteins. Indeed, we find that NLG-1⌬B recruits more axonal ␣-NRX. Our results suggest that the engagement of ␣-NRX is a key to rapid induction of synapses at new sites of axo-dendritic contact.
Neuroligin Expressed in Nonneuronal Cells Triggers Presynaptic Development in Contacting Axons
Cell, 2000
formation in the central nervous system (CNS) are not known. While agrin is found at central synapses, mice lacking agrin do not show any defects in CNS synaptogenesis (Serpinskaya et al., 1999). Other proteins that have been suggested to mediate CNS synaptogenesis Summary the spider venom ␣-latrotoxin, which triggers massive neurotransmitter release . Unfor-Most neurons form synapses exclusively with other tunately, it has so far not been possible to localize neuneurons, but little is known about the molecular mechrexins in the mammalian CNS at the ultrastructural level, anisms mediating synaptogenesis in the central nerand their synaptic localization therefore remains to be vous system. Using an in vitro system, we demonstrate demonstrated. Thousands of neurexin variants are genthat neuroligin-1 and -2, postsynaptically localized erated through alternative splicing, and this molecular proteins, can trigger the de novo formation of presyndiversity has been hypothesized to generate specificity aptic structure. Nonneuronal cells engineered to exduring synaptogenesis (Missler et al., 1998). More repress neuroligins induce morphological and functional cently, other proteins with sequence similarity to neupresynaptic differentiation in contacting axons. This rexin-1, -2, and -3 have been identified and were shown activity can be inhibited by addition of a soluble version to mediate interactions between axons and glia cells of -neurexin, a receptor for neuroligin. Furthermore, (reviewed in Bellen et al., 1998). Since these proteins addition of soluble -neurexin to a coculture of defined only partially share the domain structure of neurexin-1, pre-and postsynaptic CNS neurons inhibits synaptic -2, and -3, it is unclear whether they are bona fide neuvesicle clustering in axons contacting target neurons. rexins (Missler et al., 1998). Our results suggest that neuroligins are part of the While the presynaptic localization of neurexins remachinery employed during the formation and remodmains to be demonstrated, neuroligin-1, a ligand of a eling of CNS synapses. specific splice variant of -neurexins, has been clearly shown to localize to the postsynaptic compartment at Introduction excitatory synapses (Song et al., 1999). So far, three neuroligin genes have been described in the rat, and The excitable cells of the nervous system are joined into the predicted products of these genes are 52% identical a network by connections called synapses (Sherrington, at the amino acid level (Ichtchenko et al., 1995, 1996). 1906). This synaptic network develops as axons extend Structurally, neuroligins possess in their cytoplasmic from presynaptic neurons and grow to reach their cordomain a PDZ binding motif that mediates interactions rect postsynaptic partners. Extending axons are guided with synaptic scaffolding proteins such as PSD-95 (Irie along specific trajectories and by cues present in their et al., 1997). The extracellular domain of neuroligins conimmediate environment (Sanes and Yamagata, 1999).