Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number

1] Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [2] Max Planck Florida Institute, Jupiter, Florida, USA.
Nature Neuroscience (Impact Factor: 16.1). 11/2012; 15(12). DOI: 10.1038/nn.3256
Source: PubMed


Members of the neuroligin family of cell-adhesion proteins are found at excitatory and inhibitory synapses and are mutated in some familial forms of autism spectrum disorders. Although they display synaptogenic properties in heterologous systems, the function of neuroligins in vivo in the regulation of synapse formation and synapse number has been difficult to establish. We found that neuroligin-1 (NL1), which is located at excitatory postsynaptic densities, regulates activity-dependent synaptogenesis and mature synapse number on cortical layer 2/3 pyramidal neurons in vivo. However, synapse number was not sensitive to absolute NL1 levels but instead depended on transcellular differences in the relative amounts of NL1. These effects were independent of the cell-autonomous regulation of NMDA-type glutamate receptors by absolute levels of NL1. Our data indicate that transcellular competitive processes govern synapse formation and number in developing cortex and that NL1 has a central function in these processes.

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Available from: Jessica L Saulnier, Jul 15, 2014
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    • "Electrophysiologically, NL1 KOs and knockdowns in hippocampal neurons induced a decrease in synaptic responses mediated by NMDA receptors (NMDARs) but not by AMPA receptors (AMPARs; Chubykin et al., 2007; Kim et al., 2008; Blundell et al., 2010; Kwon et al., 2012; Soler-Llavina et al., 2011; Shipman and Nicoll, 2012). 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). "
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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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    • "in acute slices ) and NL1 expression levels manipulated by diverse strategies . In general , overexpression increases the NMDA / AMPA ratio whereas knockdown or knockout strategies result in decreases in NMDA / AMPA ratio ( Chubykin et al . , 2007 ; Futai et al . , 2007 ; Kim et al . , 2008b ; Jung et al . , 2010 ; Soler - Llavina et al . , 2011 ; Kwon et al . , 2012 ; Budreck et al . , 2013 ) . Because NL1 KO mice exhibit reduced NMDA / AMPA ratio in MSNs in the striatum ( Blundell et al . , 2010 ) , we further examined NMDA / AMPA ratio specifically in DR1 or in DR2 MSNs of WT and NL1 KO mice . To limit stimulation to local fibers , stimulation intensities were adjusted to elicit fast AMPA eEPSCs "
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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
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    • "Indeed, a recent study showed that defects in synaptogenesis and thus in synapse number observed in NLGN1-deficient neurons depend on the level of NLGN1 expression in neighboring neurons (Kwon et al., 2012). Using this model, cells with a higher NLGN1 level were favored in synapse formation and thus in establishing connections with presynaptic neurons in comparison to neighboring neurons not expressing NLGN1 (Kwon et al., 2012). This may have produced some degree of between-cell competition for neuronal targets in HET mice, where different levels of NLGN1 were expressed, which could have involved units regulating cerebrovascular parameters. "
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    ABSTRACT: Neuroligin 1 (NLGN1) is a postsynaptic adhesion molecule that determines N-methyl-D-aspartate receptor (NMDAR) function and cellular localization. Our recent work showed that Nlgn1 knockout (KO) mice cannot sustain neuronal activity occurring during wakefulness for a prolonged period of time. Since NMDAR-dependent neuronal activity drives an important vascular response, we used multispectral optical imaging to determine if the hemodynamic response to neuronal stimulation is modified in Nlgn1 KO mice. We observed that Nlgn1 KO mice show a 10% lower response rate to forepaw electrical stimulation compared to wild-type and heterozygote littermates on both the contra- and ipsilateral sides of the somatosensory cortex. Moreover, Nlgn1 mutant mice showed an earlier oxyhemoglobin (HbO) peak response that tended to return to baseline faster than in wild-type mice. Analysis of the time course of the hemodynamic response also showed that heterozygous mice express a faster dynamics of cerebrovascular response in comparison to wild-type. Taken together, these data are indicative of an altered immediate response of the brain to peripheral stimulation in Nlgn1 KO mice, and suggest a role for NLGN1 in the regulation of cerebrovascular responses. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 01/2015; 289. DOI:10.1016/j.neuroscience.2014.12.069 · 3.36 Impact Factor
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