Neuroligin-3-deficient mice: Model of a monogenic heritable form of autism with an olfactory deficit

Division of Clinical Neuroscience, Max Planck Institute for Experimental Medicine, Göttingen, Germany.
Genes Brain and Behavior (Impact Factor: 3.66). 03/2009; 8(4):416-425. DOI: 10.1111/j.1601-183X.2009.00487.x


Autism spectrum disorder (ASD) is a frequent neurodevelopmental disorder characterized by variable clinical severity. Core symptoms are qualitatively impaired communication and social behavior, highly restricted interests and repetitive behaviors. Although recent work on genetic mutations in ASD has shed light on the pathophysiology of the disease, classifying it essentially as a synaptopathy, no treatments are available to date. To develop and test novel ASD treatment approaches, validated and informative animal models are required. Of particular interest, in this context are loss-of-function mutations in the postsynaptic cell adhesion protein neuroligin-4 and point mutations in its homologue neuroligin-3 (NL-3) that were found to cause certain forms of monogenic heritable ASD in humans. Here, we show that NL-3-deficient mice display a behavioral phenotype reminiscent of the lead symptoms of ASD: reduced ultrasound vocalization and a lack of social novelty preference. The latter may be related to an olfactory deficiency observed in the NL-3 mutants. Interestingly, such olfactory phenotype is also present in a subgroup of human ASD patients. Tests for learning and memory showed no gross abnormalities in NL-3 mutants. Also, no alterations were found in time spent in social interaction, prepulse inhibition, seizure propensity and sucrose preference. As often seen in adult ASD patients, total brain volume of NL-3 mutant mice was slightly reduced as assessed by magnetic resonance imaging (MRI). Our findings show that the NL-3 knockout mouse represents a useful animal model for understanding pathophysiological events in monogenic heritable ASD and for developing novel treatment strategies in this devastating human disorder.

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Available from: Julia Fischer, Oct 13, 2014
    • "Chadman et al. (2008)found no differences in sociability across several different paradigms in Nlgn3 (R451C) mice, while Karvat and Kimchi (2012) also found no difference in social interaction or stereotyped behaviors. Nlgn3 knockout mice have shown phenotypes relevant to ASD, including impaired social memory and olfaction, hyperactivity in an open field and reduced fear memory (Radyushkin et al. 2009). "
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    ABSTRACT: Autistic spectrum disorder (ASD) is a common, chronic psychiatric disorder for which the current generation of therapeutics are limited in their success at alleviating the neurobehaviors. While it is well established that both genetic and environmental factors contribute to the disorder, there is a lack of understanding about how ASD alters multiple domains of brain function. Identifying genes that are associated with ASD, and then relating how these genetic alterations affect brain structure and function is important to furthering our ability to design treatment and prevention strategies. Recent genome screening using copy number variant (CNV) analysis has identified deletions and duplications within the neurexin and neuroligin genes in patients with ASDs, highlighting their potential importance in ASD research. Neurexins and neuroligins are synaptic cell adhesion molecules and are found at the presynapse and postsynapse, respectively, of both excitatory and inhibitory cells. Neuroligins and leucine-rich repeat transmembranes bind to neurexins and convey a role in synaptic function and maintenance. However, little is known about how alterations within the genes encoding these proteins disrupt biological processes. Here we discuss the functional role of neurexins and neuroligins, the genetic evidence for their involvement in ASD and studies with transgenic mice to elucidate the consequences of these mutations.
    The Molecular Basis of Autism, Edited by S. Hossein Fatemi, 03/2015: chapter The Role of Neurexins and Neuroligins in Autism: pages 361-381; Springer New York., ISBN: 978-1-4939-2189-8
    • "A recent study shows that both NLGN3 R451C mutant mice and NLGN3 knock-out mice disrupt tonic endocannabinoid signaling (Földy et al. 2013). Besides, impairments in social interactions, social memory, ultrasonic vocalization and olfaction, heterosynaptic competition, and perturbed metabotropic glutamate receptor-dependent synaptic plasticity were exhibited by NLGN3 knock-out mice (Radyushkin et al. 2009; Tabuchi et al. 2007; Baudouin et al. 2012). The R451C knock-in mice exhibited enhanced spatial learning ability and increased NMDA/AMPA ratio and NMDA receptor-dependent LTP in the CA1 region of the hippocampus which was not consistent with exhibitions of NLGN3 knock-out mice (Tabuchi et al. 2007; Etherton et al. 2011). "
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    ABSTRACT: Autism is a neurodevelopmental disorder with a strong genetic predisposition. Neurolign 3 (NLGN3) as a postsynaptic transmembrane protein, functions in both neuron synaptogenesis and glia-neuron communications. Previously, a gain of function mutation (R451C) in NLGN3 was identified in autistic patients, which illustrates the involvement of NLGN3 in autism pathogenesis. As proper synaptic targeting and functioning are controlled by intracellular protein interactions, in the current study, we tried to discover the intracellular regulation network in which NLGN3 might be involved by a yeast two-hybrid-based interactor identification. Fifty-one protein candidate partners were identified after screening a human fetal complementary DNA (cDNA) library with an intracellular fragment of NLGN3. The interactions of NLGN3 with a subset of candidates, including EEF1A1, FLNA, ITPRIP, CYP11A1, MT-CO2, GPR175, ACOT2, and QPRT, were further validated in human neuroblastoma cells or brain tissues. Furthermore, our study suggested that NLGN3 was functioning in cytosolic calcium balance and participating in calcium-regulated cellular processes. Our findings of novel NLGN3 binding partners provide evidences of involvement of NLGN3 in multiple biological pathways, especially calcium regulating and mitochondrial function, thus suggesting further significance. This new data not only leads to a better understanding of the physiological functions of NLGN3, but also provide new aspects for pathogenesis of autism.
    Journal of Molecular Neuroscience 12/2014; 56(1). DOI:10.1007/s12031-014-0470-9 · 2.34 Impact Factor
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    • "For instance, neuroligin-3 knockout mice show abnormalities in social memory that may be linked to an olfactory deficiency [Radyushkin et al., 2009]. As female mate preference requires social interaction and sensory perception , it may not be surprising that neuroligin-3 expression showed a much higher number of brain regions with correlated expressions relative to neuroserpin. "
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    ABSTRACT: Choosing mates is a commonly shared behavior across many organisms, with important fitness consequences. Variations in female preferences can be due in part to differences in neural and cellular activity during mate selection. Initial studies have begun to identify putative brain regions involved in mate preference, yet the understanding of the neural processes regulating these behaviors is still nascent. In this study, we characterized the expression of a gene involved in synaptogenesis and plasticity (neuroligin-3) and one that codes for the rate-limiting enzyme in dopamine biosynthesis (tyrosine hydroxylase; TH1) in the female Xiphophorus nigrensis (northern swordtail) brain as related to mate preference behavior. We exposed females to a range of different mate choice contexts including two large courting males (LL), two small coercive males (SS), and a context that paired a large courting male with a small coercive male (LS). Neuroligin-3 expression in a mate preference context (LS) showed significant correlations with female preference in two telencephalic areas (Dm and Dl), a hypothalamic nucleus (HV), and two regions associated with sexual and social behavior (POA and Vv). We did not observe any context- or behavior-specific changes in tyrosine hydroxylase mRNA expression concomitant with female preference in any of the brain regions examined. Analysis of TH and neuroligin-3 expression across different brain regions showed that expression patterns varied with the male social environment only for neuroligin-3, where the density of correlated expression between brain regions was positively associated with mate choice contexts that involved a greater number of courting male phenotypes (LS and LL). This study identified regions showing presumed high levels of synaptic plasticity using neuroligin-3, implicating and supporting their roles in female mate preference, but we did not detect any relationship between tyrosine hydroxylase and mate preference with 30 min of stimulus presentation in X. nigrensis. These data suggest that information about potential mates is processed in select forebrain regions and the entire brain shows different degrees of correlated expression depending on the mate preference context. © 2014 S. Karger AG, Basel.
    Brain Behavior and Evolution 05/2014; 83(3):231-243. DOI:10.1159/000360071 · 2.01 Impact Factor
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