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
Source: PubMed


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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    • "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.
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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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    • "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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