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Varun Kilaru - One of the best experts on this subject based on the ideXlab platform.

  • genome wide gene based analysis suggests an association between neuroligin 1 NLGN1 and post traumatic stress disorder
    Translational Psychiatry, 2016
    Co-Authors: Varun Kilaru, Bekh Bradley, Lynn M Almli, Nastassja Koen, S.v. Iyer, Adriana Lori, Elisabeth B. Binder, Tanja Jovanovic, Jennifer S Stevens, Dan J. Stein
    Abstract:

    Genome-wide gene-based analysis suggests an association between Neuroligin 1 ( NLGN1 ) and post-traumatic stress disorder

  • genome wide gene based analysis suggests an association between neuroligin 1 NLGN1 and post traumatic stress disorder
    Translational Psychiatry, 2016
    Co-Authors: Varun Kilaru, Bekh Bradley, Lynn M Almli, S.v. Iyer, Adriana Lori, Elisabeth B. Binder, Tanja Jovanovic, Jennifer S Stevens, T D Ely, Nastassja Koen
    Abstract:

    Post-traumatic stress disorder (PTSD) develops in only some people following trauma exposure, but the mechanisms differentially explaining risk versus resilience remain largely unknown. PTSD is heritable but candidate gene studies and genome-wide association studies (GWAS) have identified only a modest number of genes that reliably contribute to PTSD. New gene-based methods may help identify additional genes that increase risk for PTSD development or severity. We applied gene-based testing to GWAS data from the Grady Trauma Project (GTP), a primarily African American cohort, and identified two genes (NLGN1 and ZNRD1-AS1) that associate with PTSD after multiple test correction. Although the top SNP from NLGN1 did not replicate, we observed gene-based replication of NLGN1 with PTSD in the Drakenstein Child Health Study (DCHS) cohort from Cape Town. NLGN1 has previously been associated with autism, and it encodes neuroligin 1, a protein involved in synaptogenesis, learning, and memory. Within the GTP dataset, a single nucleotide polymorphism (SNP), rs6779753, underlying the gene-based association, associated with the intermediate phenotypes of higher startle response and greater functional magnetic resonance imaging activation of the amygdala, orbitofrontal cortex, right thalamus and right fusiform gyrus in response to fearful faces. These findings support a contribution of the NLGN1 gene pathway to the neurobiological underpinnings of PTSD.

Nastassja Koen - One of the best experts on this subject based on the ideXlab platform.

  • genome wide gene based analysis suggests an association between neuroligin 1 NLGN1 and post traumatic stress disorder
    Translational Psychiatry, 2016
    Co-Authors: Varun Kilaru, Bekh Bradley, Lynn M Almli, Nastassja Koen, S.v. Iyer, Adriana Lori, Elisabeth B. Binder, Tanja Jovanovic, Jennifer S Stevens, Dan J. Stein
    Abstract:

    Genome-wide gene-based analysis suggests an association between Neuroligin 1 ( NLGN1 ) and post-traumatic stress disorder

  • genome wide gene based analysis suggests an association between neuroligin 1 NLGN1 and post traumatic stress disorder
    Translational Psychiatry, 2016
    Co-Authors: Varun Kilaru, Bekh Bradley, Lynn M Almli, S.v. Iyer, Adriana Lori, Elisabeth B. Binder, Tanja Jovanovic, Jennifer S Stevens, T D Ely, Nastassja Koen
    Abstract:

    Post-traumatic stress disorder (PTSD) develops in only some people following trauma exposure, but the mechanisms differentially explaining risk versus resilience remain largely unknown. PTSD is heritable but candidate gene studies and genome-wide association studies (GWAS) have identified only a modest number of genes that reliably contribute to PTSD. New gene-based methods may help identify additional genes that increase risk for PTSD development or severity. We applied gene-based testing to GWAS data from the Grady Trauma Project (GTP), a primarily African American cohort, and identified two genes (NLGN1 and ZNRD1-AS1) that associate with PTSD after multiple test correction. Although the top SNP from NLGN1 did not replicate, we observed gene-based replication of NLGN1 with PTSD in the Drakenstein Child Health Study (DCHS) cohort from Cape Town. NLGN1 has previously been associated with autism, and it encodes neuroligin 1, a protein involved in synaptogenesis, learning, and memory. Within the GTP dataset, a single nucleotide polymorphism (SNP), rs6779753, underlying the gene-based association, associated with the intermediate phenotypes of higher startle response and greater functional magnetic resonance imaging activation of the amygdala, orbitofrontal cortex, right thalamus and right fusiform gyrus in response to fearful faces. These findings support a contribution of the NLGN1 gene pathway to the neurobiological underpinnings of PTSD.

Toru Takumi - One of the best experts on this subject based on the ideXlab platform.

  • functional significance of rare neuroligin 1 variants found in autism
    PLOS Genetics, 2017
    Co-Authors: Moe Nakanishi, Jun Nomura, Xiao Ji, Kota Tamada, Takashi Arai, Eiki Takahashi, Maja Bucan, Toru Takumi
    Abstract:

    Genetic mutations contribute to the etiology of autism spectrum disorder (ASD), a common, heterogeneous neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive and restricted patterns of behavior. Since neuroligin3 (NLGN3), a cell adhesion molecule at the neuronal synapse, was first identified as a risk gene for ASD, several additional variants in NLGN3 and NLGN4 were found in ASD patients. Moreover, synaptopathies are now known to cause several neuropsychiatric disorders including ASD. In humans, NLGNs consist of five family members, and neuroligin1 (NLGN1) is a major component forming a complex on excitatory glutamatergic synapses. However, the significance of NLGN1 in neuropsychiatric disorders remains unknown. Here, we systematically examine five missense variants of NLGN1 that were detected in ASD patients, and show molecular and cellular alterations caused by these variants. We show that a novel NLGN1 Pro89Leu (P89L) missense variant found in two ASD siblings leads to changes in cellular localization, protein degradation, and to the impairment of spine formation. Furthermore, we generated the knock-in P89L mice, and we show that the P89L heterozygote mice display abnormal social behavior, a core feature of ASD. These results, for the first time, implicate rare variants in NLGN1 as functionally significant and support that the NLGN synaptic pathway is of importance in the etiology of neuropsychiatric disorders.

  • In silico investigation of NLGN1 variants observed in patients with ASD.
    2017
    Co-Authors: Moe Nakanishi, Jun Nomura, Kota Tamada, Takashi Arai, Eiki Takahashi, Maja Bućan, Toru Takumi
    Abstract:

    (A) Ribbon diagram of the extracellular part of the mouse NLGN1 dimer viewed from the side, based on Protein Data Bank (PDB) entry 3B3Q. The dotted line shows the NLGN1 region for which crystal structure is unavailable. Amino-acid numberings of mouse NLGN1 (human NLGN1) are indicated. The variants assessed in this study are shown in red. The gray box indicates the location of a proline-rich loop of NLGN1. (B) Ribbon diagram of the NLGN1-NRXN1β complex, viewed from the post-synaptic membrane with variants. (C) Enlarged image of the proline-rich loop structure of NLGN1 in which P89 is located (shown in light blue). Previously identified NLGN4 missense variants (G84R, R87W, and G99S) found in ASD are also indicated. (D) The protein alignment of the NLGN1-4 family. The highly conserved P89 residue, mutated in ASD patients, is boxed in red, and pathogenic NLGN4 variants, localized in the same loop, are shown as blue arrows.

  • Pathogenic NLGN1 variants exhibit abnormal sub-localization and expression.
    2017
    Co-Authors: Moe Nakanishi, Jun Nomura, Kota Tamada, Takashi Arai, Eiki Takahashi, Maja Bućan, Toru Takumi
    Abstract:

    (A) Fluorescence images of COS7 cells transfected WT or mutant NLGN1 with HA-tag. Endoplasmic reticulum (ER) was stained with calnexin. Three pathogenic variants (P89L, L269P, and G288E) were trapped in ER, and failed to traffic the plasma membrane. Scale bar indicates 10 μm. (B) Representative images of western blots of cell lysates from COS7 cells transfected with HA-tagged NLGN1. NLGN1 was detected by anti-HA tag. The expected molecular weight for the NLGN1: glycosylated mature NLGN1 (~110 kDa), non-glycosylated immature NLGN1 (~100 kDa). (C) Quantitative analysis of the western blots for total (left) and glycosylated (right) NLGN1. The expression of NLGN1 variants is normalized to the corresponding β-actin. NLGN1 variants observed in ASD subjects showed decreased expression level compared to WT. Data represents mean ± S.E.M. of four samples from three independent experiments (one-way ANOVA followed by Tukey-Kramer’s multiple comparisons test, *p

  • Impaired spine induction by NLGN1 variants observed in patients with ASD.
    2017
    Co-Authors: Moe Nakanishi, Jun Nomura, Kota Tamada, Takashi Arai, Eiki Takahashi, Maja Bućan, Toru Takumi
    Abstract:

    (A) Representative fluorescence images of hippocampal neurons (DIV14) co-transfected with negative control, WT, and non-pathogenic NLGN1 or pathogenic NLGN1 variants with GFP expression vector. NLGN1 expression of pathogenic variants (P89L, L269P, G288E, and H786Y) was decreased compared to others. (B) Representative images of spines from neurons transfected with negative control, WT, and non-pathogenic NLGN1 or pathogenic variants of NLGN1. (C) Quantification of the number of spines. Spine number in dendrite was significantly lower in four pathogenic variants (P89L, L269P, G288E, and H786Y) compared to WT, and no significant differences between GFP-transfected control and these four variants were observed. Data represent mean ± S.E.M. (*p

  • Identification of P89L substitution in NLGN1.
    2017
    Co-Authors: Moe Nakanishi, Jun Nomura, Kota Tamada, Takashi Arai, Eiki Takahashi, Maja Bućan, Toru Takumi
    Abstract:

    (A) Pedigree of the family harboring the NLGN1 c.266C>T (p.Pro89Leu) substitution. (B) Sequence electropherograms of family AU0729. Father (1), Mother (2), unaffected sibling (3), affected siblings (4 and 5). Arrows indicate the location of the NLGN1 c.266C>T substitution.

Dan J. Stein - One of the best experts on this subject based on the ideXlab platform.

Valerie Mongrain - One of the best experts on this subject based on the ideXlab platform.

  • the effect of neuroligin 2 absence on sleep architecture and electroencephalographic activity in mice
    Molecular Brain, 2018
    Co-Authors: Bong Soo Seok, Erika Belangernelson, Chloe Provost, Steve A Gibbs, Valerie Mongrain
    Abstract:

    Sleep disorders are comorbid with most psychiatric disorders, but the link between these is not well understood. Neuroligin-2 (NLGN2) is a cell adhesion molecule that plays roles in synapse formation and neurotransmission. Moreover, NLGN2 has been associated with psychiatric disorders, but its implication in sleep remains underexplored. In the present study, the effect of Nlgn2 knockout (Nlgn2−/−) on sleep architecture and electroencephalographic (EEG) activity in mice has been investigated. The EEG and electromyogram (EMG) were recorded in Nlgn2−/− mice and littermates for 24 h from which three vigilance states (i.e., wakefulness, rapid eye movement [REM] sleep, non-REM [NREM] sleep) were visually identified. Spectral analysis of the EEG was performed for the three states. Nlgn2−/− mice showed more wakefulness and less NREM and REM sleep compared to wild-type (Nlgn2+/+) mice, especially during the dark period. This was accompanied by changes in the number and duration of individual episodes of wakefulness and sleep, indexing changes in state consolidation, as well as widespread changes in EEG spectral activity in all states. Abnormal ‘hypersynchronized’ EEG events have also been observed predominantly in Nlgn2−/− mice. These events were mainly observed during wakefulness and REM sleep. In addition, Nlgn2−/− mice showed alterations in the daily time course of NREM sleep delta (1–4 Hz) activity, pointing to modifications in the dynamics of sleep homeostasis. These data suggest that NLGN2 participates in the regulation of sleep duration as well as EEG activity during wakefulness and sleep.

  • regulation of the neuroligin 1 gene by clock transcription factors
    Journal of Biological Rhythms, 2018
    Co-Authors: Lydia Hannou, Erika Belangernelson, Emma K Ocallaghan, Julien Dufortgervais, Maria Neus Ballester Roig, Nicolas Cermakian, Jeanmartin Beaulieu, Valerie Mongrain
    Abstract:

    NEUROLIGIN-1 (NLGN1) is a postsynaptic adhesion molecule involved in the regulation of glutamatergic transmission. It has been associated with several features of sleep and psychiatric disorders. O...

  • brain hemodynamic response to somatosensory stimulation in neuroligin 1 knockout mice
    Neuroscience, 2015
    Co-Authors: Erika Belangernelson, Marlene Freyburger, Eric Beaumont, Frederic Lesage, Philippe Pouliot, Valerie Mongrain
    Abstract:

    Abstract Neuroligin 1 (NLGN1) is a postsynaptic adhesion molecule that determines N-methyl- d -aspartate receptor (NMDAR) function and cellular localization. Our recent work showed that NLGN1 knockout (KO) mice cannot sustain neuronal activity occurring during wakefulness for a prolonged period of time. Since NMDAR-dependent neuronal activity drives an important vascular response, we used multispectral optical imaging to determine if the hemodynamic response to neuronal stimulation is modified in NLGN1 KO mice. We observed that NLGN1 KO mice show a 10% lower response rate to forepaw electrical stimulation compared to wild-type (WT) and heterozygote (HET) littermates on both the contra- and ipsilateral sides of the somatosensory cortex. Moreover, NLGN1 mutant mice showed an earlier oxyhemoglobin peak response that tended to return to baseline faster than in WT mice. Analysis of the time course of the hemodynamic response also showed that HET mice express a faster dynamics of cerebrovascular response in comparison to WT. Taken together, these data are indicative of an altered immediate response of the brain to peripheral stimulation in NLGN1 KO mice, and suggest a role for NLGN1 in the regulation of cerebrovascular responses.