Dahlhaus R, Hines RM, Eadie BD, Kannangara TS, Hines DJ, Brown CE et al. Overexpression of the cell adhesion protein neuroligin-1 induces learning deficits and impairs synaptic plasticity by altering the ratio of excitation to inhibition in the hippocampus. Hippocampus 20: 305-322

Department of Psychiatry, University of British Columbia, Vancouver, BC.
Hippocampus (Impact Factor: 4.16). 02/2009; 20(2):305-22. DOI: 10.1002/hipo.20630
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Trans-synaptic cell-adhesion molecules have been implicated in regulating CNS synaptogenesis. Among these, the Neuroligin (NL) family (NLs 1-4) of postsynaptic adhesion proteins has been shown to promote the development and specification of excitatory versus inhibitory synapses. NLs form a heterophilic complex with the presynaptic transmembrane protein Neurexin (NRX). A differential association of NLs with postsynaptic scaffolding proteins and NRX isoforms has been suggested to regulate the ratio of excitatory to inhibitory synapses (E/I ratio). Using transgenic mice, we have tested this hypothesis by overexpressing NL1 in vivo to determine whether the relative levels of these cell adhesion molecules may influence synapse maturation, long-term potentiation (LTP), and/or learning. We found that NL1-overexpressing mice show significant deficits in memory acquisition, but not in memory retrieval. Golgi and electron microscopy analysis revealed changes in synapse morphology indicative of increased maturation of excitatory synapses. In parallel, electrophysiological examination indicated a shift in the synaptic activity toward increased excitation as well as impairment in LTP induction. Our results demonstrate that altered balance in the expression of molecules necessary for synapse specification and development (such as NL1) can lead to defects in memory formation and synaptic plasticity and outline the importance of rigidly controlled synaptic maturation processes.

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Available from: Brian R Christie, Oct 07, 2015
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    • "ipman et al . , 2011 ; Soler - Llavina et al . , 2011 ; Kwon et al . , 2012 ; Shipman and Nicoll , 2012 ; Hoy et al . , 2013 ; Bie et al . , 2014 ) . Also , even though NL1 is a postsynaptic protein , altering its expression levels also has presynaptic consequences including effects on clustering of synaptic vesicles ( Wittenmayer et al . , 2009 ; Dahlhaus et al . , 2010 ) and on the frequency of spontaneous miniature excitatory postsynaptic currents ( mEPSCs ; Prange et al . , 2004 ; Nam and Chen , 2005 ; Chen et al . , 2010 ; Mondin et al . , 2011 ; Burton et al . , 2012 ; Kwon et al . , 2012 ; Schnell et al . , 2012 ) . The basal ganglia ( BG ) are an essential component of larger parallel circuits i"
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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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    • "For details of the cultivation of human embryonic kidney (HEK-293) cells and primary hippocampal neurons as well as of immunhistochemistry experiments involving HEK-293 cells, neurons, and brain slices, please refer Derlig et al. (2013) and Dahlhaus et al. (2010). Live cell imaging was implemented using a laser scanning microscope (LSM 710, Zeiss) and ZEN 2010 software with corresponding imaging modules. "
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    ABSTRACT: The Actin cytoskeleton constitutes the functional base for a multitude of cellular processes extending from motility and migration to cell mechanics and morphogenesis. The latter is particularly important to neuronal cells since the accurate functioning of the brain crucially depends on the correct arborization of neurons, a process that requires the formation of several dozens to hundreds of dendritic branches. Recently, a model was proposed where different transcription factors are detailed to distinct facets and phases of dendritogenesis and exert their function by acting on the Actin cytoskeleton, however, the proteins involved as well as the underlying molecular mechanisms are largely unknown. Here, we demonstrate that Simiate, a protein previously indicated to activate transcription, directly associates with both, G- and F-Actin and in doing so, affects Actin polymerization and Actin turnover in living cells. Imaging studies illustrate that Simiate particularly influences filopodia dynamics and specifically increases the branching of proximal, but not distal dendrites of developing neurons. The data suggests that Simiate functions as a direct molecular link between transcription regulation on one side, and dendritogenesis on the other, wherein Simiate serves to coordinate the development of proximal and distal dendrites by acting on the Actin cytoskeleton of filopodia and on transcription regulation, hence supporting the novel model.
    Frontiers in Cellular Neuroscience 04/2014; 8(1):99. DOI:10.3389/fncel.2014.00099 · 4.29 Impact Factor
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    • "All spins during the procedure were carried out at 500g and 4°C for 1min. Cell lysates from various tissues were prepared as published previously [41] and kept with the coated matrix overnight at 4°C end over end. Hereafter, the samples were washed 3x with Hepes-buffer before all retained proteins were eluted for 10min at 60°C with 4xSDS buffer (20% SDS, 40% glycerol, 250mM TRIS, pH 6.8) and analysed using specific antibodies to detect proteins of interest by western blotting. "
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    ABSTRACT: A strict regulation of protein expression during developmental stages and in response to environmental signals is essential to every cell and organism. Recent research has shown that the mammalian brain is particularly sensitive to alterations in expression patterns of specific proteins and cognitive deficits as well as autistic behaviours have been linked to dysregulated protein expression. An intellectual disability characterised by changes in the expression of a variety of proteins is the fragile X syndrome. Due to the loss of a single mRNA binding protein, the Fragile X Mental Retardation Protein FMRP, vast misregulation of the mRNA metabolism is taking place in the disease. Here, we present the identification and characterisation of a novel protein named Simiate, whose mRNA contains several FMRP recognition motifs and associates with FMRP upon co-precipitation. Sequence analysis revealed that the protein evolved app. 1.7 billion years ago when eukaryotes developed. Applying antibodies generated against Simiate, the protein is detected in a variety of tissues, including the mammalian brain. On the subcellular level, Simiate localises to somata and nuclear speckles. We show that Simiate and nuclear speckles experience specific alterations in FMR1(-/-) mice. An antibody-based block of endogenous Simiate revealed that the protein is essential for cell survival. These findings suggest not only an important role for Simiate in gene transcription and/or RNA splicing, but also provide evidence for a function of nuclear speckles in the fragile X syndrome. Indeed, transcription and splicing are two fundamental mechanisms to control protein expression, that underlie not only synaptic plasticity and memory formation, but are also affected in several diseases associated with mental disabilities.
    PLoS ONE 12/2013; 8(12):e83007. DOI:10.1371/journal.pone.0083007 · 3.23 Impact Factor
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