Selective capability of SynCAM and neuroligin for functional synapse assembly

Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2005; 25(1):260-70. DOI: 10.1523/JNEUROSCI.3165-04.2005
Source: PubMed


Synaptic cell adhesion is central for synapse formation and function. Recently, the synaptic cell adhesion molecules neuroligin 1 (NL1) and SynCAM were shown to induce presynaptic differentiation in cocultured neurons when expressed in a non-neuronal cell. However, it is uncertain how similar the resulting artificial synapses are to regular synapses. Are these molecules isofunctional, or do all neuronal cell adhesion molecules nonspecifically activate synapse formation? To address these questions, we analyzed the properties of artificial synapses induced by NL1 and SynCAM, compared the actions of these molecules with those of other neuronal cell adhesion molecules, and examined the functional effects of NL1 and SynCAM overexpression in neurons. We found that only NL1 and SynCAM specifically induced presynaptic differentiation in cocultured neurons. The induced nerve terminals were capable of both spontaneous and evoked neurotransmitter release, suggesting that a full secretory apparatus was assembled. By all measures, SynCAM- and NL1-induced artificial synapses were identical. Overexpression in neurons demonstrated that only SynCAM, but not NL1, increased synaptic function in immature developing excitatory neurons after 8 d in vitro. Tests of chimeric molecules revealed that the dominant-positive effect of SynCAM on synaptic function in developing neurons was mediated by its intracellular cytoplasmic tail. Interestingly, morphological analysis of neurons overexpressing SynCAM or NL1 showed the opposite of the predictions from electrophysiological results. In this case, only NL1 increased the synapse number, suggesting a role for NL1 in morphological synapse induction. These results suggest that both NL1 and SynCAM act similarly and specifically in artificial synapse induction but that this process does not reflect a shared physiological function of these molecules.

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Available from: Deniz Atasoy, Aug 21, 2014
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    • "In contrast, NL2 and NL3 KOs caused selective impairments in subsets of GABAergic synapses (Chubykin et al., 2007; Gibson et al., 2009; Poulopoulos et al., 2009; Etherton et al., 2011; Fö ldy et al., 2013; Rothwell et al., 2014). Overexpression of all neuroligin isoforms, conversely, increased synapse numbers as assessed morphologically (Boucard et al., 2005; Chih et al., 2005; Ko et al., 2009b; Sara et al., 2005; Zhang et al., 2009). In addition, overexpression of NL1 enhanced both NMDAR-and AMPAR-mediated excitatory postsynaptic currents (EPSCs), overexpression of NL2 selectively increased inhibitory postsynaptic currents (IPSCs), and overexpression of NL4 paradoxically decreased NMDAR-and AMPAR-mediated EPSCs, whereas overexpression of NL3 produced no electrophysiological effect (Chubykin et al., 2007; Ko et al., 2009b; Zhang et al., 2009; Chanda et al., 2013). "
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    ABSTRACT: Neuroligins are postsynaptic cell-adhesion molecules that bind presynaptic neurexins and are genetically linked to autism. Neuroligins are proposed to organize synaptogenesis and/or synaptic transmission, but no systematic analysis of neuroligins in a defined circuit is available. Here, we show that conditional deletion of all neuroligins in cerebellar Purkinje cells caused loss of distal climbing-fiber synapses and weakened climbing-fiber but not parallel-fiber synapses, consistent with alternative use of neuroligins and cerebellins as neurexin ligands for the excitatory climbing-fiber versus parallel-fiber synapses. Moreover, deletion of neuroligins increased the size of inhibitory basket/stellate-cell synapses but simultaneously severely impaired their function. Multiple neuroligin isoforms differentially contributed to climbing-fiber and basket/stellate-cell synapse functions, such that inhibitory synapse-specific neuroligin-2 was unexpectedly essential for maintaining normal climbing-fiber synapse numbers. Using systematic analyses of all neuroligins in a defined neural circuit, our data thus show that neuroligins differentially contribute to various Purkinje-cell synapses in the cerebellum in vivo. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 08/2015; 87(4). DOI:10.1016/j.neuron.2015.07.020 · 15.05 Impact Factor
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    • " disease ( Saura et al . , 2011 ; Bie et al . , 2014 ) . These cell - adhesion molecules are critical for synapse specification and function via interactions with partners that constitute the neurotransmission machinery on both sides of the synapse ( Scheiffele et al . , 2000 ; Missler et al . , 2003 ; Graf et al . , 2004 ; Prange et al . , 2004 ; Sara et al . , 2005 ; Gerrow et al . , 2006 ; Chubykin et al . , 2007 ; Mukherjee et al . , 2008 ) . NL1 is specific to excitatory synapses where it promotes the retention of α - amino - 3 - hydroxyl - 5 - methyl - 4 - isoxazole - propionate receptors ( AMPARs ; Heine et al . , 2008 ; Mondin et al . , 2011 ) as well as the clustering of N - methyl - D - asp"
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    ABSTRACT: Together with its presynaptic partner Neurexin 1 (Nxn1), Neuroligin 1 (NL1) participates in synapse specification and synapse maintenance. We and others have shown that NL1 can also modulate glutamatergic synaptic function in the central nervous system of rodent models. These molecular/cellular changes can translate into altered animal behaviors that are thought to be analogous to symptomatology of neuropsychiatric disorders. For example, in dorsal striatum of NL1 deletion mice, we previously reported that the ratio N-methyl-D-aspartate receptor (NMDAR) mediated synaptic currents to a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) mediated synaptic currents (NMDA/AMPA) is reduced in medium spiny neuron (MSNs). Importantly, this reduction in NMDA/AMPA ratio correlated with increased repetitive grooming. The striatum is the input nucleus of the basal ganglia (BG). Classical models of this circuitry imply that there are two principal pathways that render distinct and somewhat opposite striatal outputs critical to the function of these nuclei in modulating motor behavior. Thus, we set out to better characterize the effects of NL1 deletion on direct and indirect pathways of the dorsal striatum by genetically labeling MSNs participating in the direct and indirect pathways. We demonstrate that a decrease in NMDAR-mediated currents is limited to MSNs of the direct pathway. Furthermore, the decrease in NMDAR-mediated currents is largely due to a reduction in function of NMDARs containing the GluN2A subunit. In contrast, indirect pathway MSNs in NL1 knockout (KO) mice showed a reduction in the frequency of miniature excitatory neurotransmission not observed in the direct pathway. Thus, NL1 deletion differentially affects direct and indirect pathway MSNs in dorsal striatum. These findings have potential implications for striatal function in NL1 KO mice.
    Frontiers in Synaptic Neuroscience 07/2015; 7(11):1-16. DOI:10.3389/fnsyn.2015.00011
    • "In addition, synapse number actually increases in β-catenin knockout mice (Bamji and others 2003), possibly due to enhanced SV distribution within the axon (Bamji and others 2006). Furthermore, n-cadherin by itself cannot induce presynaptic terminal formation , as axonal contact with a non-neuronal cell expressing n-cadherin does not lead to presynaptic terminal formation at the contact site as it does with other postsynaptic adhesion proteins such as neuroligin and SynCAM (Sara and others 2005; Scheiffele and others 2000). Despite this, n-cadherin interacts with other trans-synaptic adhesion proteins to promote their function. "
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    ABSTRACT: To create a presynaptic terminal, molecular signaling events must be orchestrated across a number of subcellular compartments. In the soma, presynaptic proteins need to be synthesized, packaged together, and attached to microtubule motors for shipment through the axon. Within the axon, transport of presynaptic packages is regulated to ensure that developing synapses receive an adequate supply of components. At individual axonal sites, extracellular interactions must be translated into intracellular signals that can incorporate mobile transport vesicles into the nascent presynaptic terminal. Even once the initial recruitment process is complete, the components and subsequent functionality of presynaptic terminals need to constantly be remodeled. Perhaps most remarkably, all of these processes need to be coordinated in space and time. In this review, we discuss how these dynamic cellular processes occur in neurons of the central nervous system in order to generate presynaptic terminals in the brain. © The Author(s) 2015.
    The Neuroscientist 07/2015; DOI:10.1177/1073858415596131 · 6.84 Impact Factor
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