A Subtype-Specific Function for the Extracellular Domain of Neuroligin 1 in Hippocampal LTP

Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
Neuron (Impact Factor: 15.05). 10/2012; 76(2):309-16. DOI: 10.1016/j.neuron.2012.07.024
Source: PubMed


At neuronal excitatory synapses, two major subtypes of the synaptic adhesion molecule neuroligin are present. These subtypes, neuroligin 1 and neuroligin 3, have roles in synaptogenesis and synaptic maintenance that appear largely overlapping. In this study, we combine electrophysiology with molecular deletion and replacement of these proteins to identify similarities and differences between these subtypes. In doing so, we identify a subtype-specific role in LTP for neuroligin 1 in young CA1, which persists into adulthood in the dentate gyrus. As neuroligin 3 showed no requirement for LTP, we constructed chimeric proteins of the two excitatory neuroligin subtypes to identify the molecular determinants particular to the unique function of neuroligin 1. Using in vivo molecular replacement experiments, we find that these unique functions depend on a region in its extracellular domain containing the B site splice insertion previously shown to determine specificity of neurexin binding.

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    • "Indeed, although all NL isoforms can induce synapse formation, NL1 but not NL3 induces the recruitment of NMDA receptors and long-term potentiation (LTP) (Budreck et al., 2013;Shipman and Nicoll, 2012), a form of synaptic plasticity associated with learning and memory and affected in AD. Interestingly, the p.Thr271fs mutation identified here resides within a critical region of NL1 that mediates LTP (Shipman and Nicoll, 2012). Moreover, depletion of NL1 in knockout mice or in adult mice with RNA interference impairs NMDA receptoremediated currents and expression of LTP (Blundell et al., 2010;Kim et al., 2008). "
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    ABSTRACT: Neuroligins (NLs) are cell-adhesion proteins that regulate synapse formation and function. Neuroligin 1 (NL1) promotes the formation of glutamatergic synapses and mediates long-term potentiation in mouse models. Thus, altered NL1 function could mediate the synaptic and memory deficits associated with Alzheimer's disease (AD). Here, we describe a frameshift mutation, c.875_876insTT, in the neuroligin 1 gene (NLGN1) in a patient with AD and familial history of AD. The insertion generates a premature stop codon in the extracellular domain of NL1 (p.Thr271fs). Expression of mutant NL1 shows accumulation of truncated NL1 proteins in the endoplasmic reticulum. In hippocampal neurons, the p.Thr271fs mutation abolishes the ability of NL1 to promote the formation of glutamatergic synapses. Our data support a role for inactivating mutations in NLGN1 in AD. Previous studies have reported rare mutations in X-linked NLGNL3 and NLGNL4 genes in patients with autism, which result in the inactivation of the mutant alleles. Therefore, together with a role in neurodevelopmental disorders, altered NL function could underlie the molecular mechanisms associated with brain diseases in the elderly.
    Full-text · Article · Oct 2015 · Neurobiology of Aging
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    • "In addition, Salm3 −/− synapses show normal levels of LTP, LTD, and late LTP. This contrasts with the reported regulation of LTP by neuroligin-1 and LRRTM1/2 (Blundell et al., 2010; Jedlicka et al., 2015; Jung et al., 2010; Kim et al., 2008; Shipman and Nicoll, 2012; Soler-Llavina et al., 2013), but is similar to the minimal LTP regulation by neuroligin-3 (Shipman and Nicoll, 2012). "
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    ABSTRACT: Synaptic adhesion molecules regulate diverse aspects of synapse development and plasticity. SALM3 is a PSD-95-interacting synaptic adhesion molecule known to induce presynaptic differentiation in contacting axons, but little is known about its presynaptic receptors and in vivo functions. Here, we identify an interaction between SALM3 and LAR family receptor protein tyrosine phosphatases (LAR-RPTPs) that requires the mini-exon B splice insert in LAR-RPTPs. In addition, SALM3-dependent presynaptic differentiation requires all three types of LAR-RPTPs. SALM3 mutant (Salm3(-/-)) mice display markedly reduced excitatory synapse number but normal synaptic plasticity in the hippocampal CA1 region. Salm3(-/-) mice exhibit hypoactivity in both novel and familiar environments but perform normally in learning and memory tests administered. These results suggest that SALM3 regulates excitatory synapse development and locomotion behavior. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Cell Reports
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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.
    Full-text · Article · Aug 2015 · Neuron
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