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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    • "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
    • "Indeed, although all NL isoforms can induce synapse formation, NL1 but not NL3 induce the recruitment of NMDA receptors and longterm 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 KO mice or in adult mice with RNA interference impairs NMDA-receptor mediated currents and expression of LTP (Blundell, et al., 2010; Kim, et al., 2008). "
    Neurobiology of Aging 01/2015; DOI:10.1016/j.neurobiolaging.2015.09.004 · 5.01 Impact Factor
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    • "These animals also showed impaired social behavior and anxiety. A study using NLGN1 and NLGN3 knockdown showed that NLGN1 alternatively spliced at site B is required for LTP expression in young CA1 pyramidal cells, but that NLGN3 does not appear essential for LTP support (Shipman and Nicoll, 2012). Neurexin and neuroligin proteins at sensory-to-motor neuron synapses play roles in the gill-withdrawal reflex in Aplysia, which exhibits sensitization (Choi et al., 2011). "
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    ABSTRACT: Synaptic damage is a critical hallmark of Alzheimer's disease, and the best correlate with cognitive impairment ante mortem. Synapses, the loci of communication between neurons, are characterized by signature protein combinations arrayed at tightly apposed pre- and post-synaptic sites. The most widely studied trans-synaptic junctional complexes, which direct synaptogenesis and foster the maintenance and stability of the mature terminal, are conjunctions of presynaptic neurexins and postsynaptic neuroligins. Fluctuations in the levels of neuroligins and neurexins can sway the balance between excitatory and inhibitory neurotransmission in the brain, and could lead to damage of synapses and dendrites. This review summarizes current understanding of the roles of neurexins and neuroligins proteolytic processing in synaptic plasticity in the human brain, and outlines their possible roles in β-amyloid metabolism and function, which are central pathogenic events in Alzheimer's disease progression.
    Neurobiology of aging 11/2013; 35(4). DOI:10.1016/j.neurobiolaging.2013.09.032 · 5.01 Impact Factor
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