Neuroligin-1 Deletion Results in Impaired Spatial Memory and Increased Repetitive Behavior

Blundell, Jacqueline; Blaiss, Cory A.; Etherton, Mark R.; Espinosa, Felipe Rafael Reyna; Tabuchi, Katsuhiko; Walz, Christopher; Bolliger, Marc; Südhof, Thomas C.; Powell, Craig M.

doi:10.1523/jneurosci.4517-09.2010

Cited by 396 publications

(407 citation statements)

References 76 publications

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“…Locomotor activity was measured in a circular corridor with four infrared beams placed at every 90°(Imetronic, Passac, France), as previously described (Blundell et al, 2010;Doly et al, 2008). Mice were injected with saline and individually placed in the activity box for 2 h during four consecutive days in order to habituate to the apparatus.…”

Section: Locomotor Response To Novelty and To Psychostimulantsmentioning

confidence: 99%

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Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

Pitychoutis

Belmer

Moutkine

et al. 2015

Neuropsychopharmacol

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Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a populationspecific serotonin 2B (5-HT 2B ) receptor stop codon (ie, HTR2B Q20*) was reported to segregate with severely impulsive individuals, whereas 5-HT 2B mutant (Htr 2B − / − ) mice also showed high impulsivity. Interestingly, in the same cohort, early-onset schizophrenia was more prevalent in HTR2B Q*20 carriers. However, the putative role of 5-HT 2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT 2B receptors in mice subjected to a comprehensive series of behavioral test screenings for schizophrenic-like symptoms and investigated relevant dopaminergic and glutamatergic neurochemical alterations in the cortex and the striatum. Domains related to the positive, negative, and cognitive symptom clusters of schizophrenia were affected in Htr 2B − / − mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions, and in learning and memory processes. In addition, Htr 2B − / − mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT 2B receptors induced a region-selective decrease of dopamine and glutamate concentrations in the dorsal striatum. Importantly, selected schizophreniclike phenotypes and endophenotypes were rescued by chronic haloperidol treatment. We report herein that 5-HT 2B receptor deficiency confers a wide spectrum of antipsychotic-sensitive schizophrenic-like behavioral and psychopharmacological phenotypes in mice and provide first evidence for a role of 5-HT 2B receptors in the neurobiology of psychotic disorders.

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Section: Locomotor Response To Novelty and To Psychostimulantsmentioning

confidence: 99%

“…Fear conditioning was assessed in computer-controlled operant chambers (Imetronic), as previously described (Blundell et al, 2010;Cai et al, 2006;Powell et al, 2004). All results were expressed as % time freezing.…”

Section: Contextual and Cued Fear Conditioningmentioning

confidence: 99%

Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

Pitychoutis

Belmer

Moutkine

et al. 2015

Neuropsychopharmacol

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“…There is accumulating evidence that global ablation of NL1 expression (as in KO mice) and the down-regulation in subsets of cells exhibit different phenotypes. Whereas suppression of NL1 in subsets of cells results in a loss of synapses in vitro and in vivo (8,31,32), global KO has little impact on synapse density but rather regulates the density of NMDARs per synapse (10,33,34). The mechanistic underpinnings of these observations remain to be resolved, but it is likely that competitive mechanisms between cells with different NL1 expression levels contribute to these phenomena (35).…”

Section: Nl1 Drives the Incorporation And Synaptic Retention Of Nmdarsmentioning

confidence: 99%

Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling

Budreck

Kwon

Jung

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

161

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Despite the pivotal functions of the NMDA receptor (NMDAR) for neural circuit development and synaptic plasticity, the molecular mechanisms underlying the dynamics of NMDAR trafficking are poorly understood. The cell adhesion molecule neuroligin-1 (NL1) modifies NMDAR-dependent synaptic transmission and synaptic plasticity, but it is unclear whether NL1 controls synaptic accumulation or function of the receptors. Here, we provide evidence that NL1 regulates the abundance of NMDARs at postsynaptic sites. This function relies on extracellular, NL1 isoform-specific sequences that facilitate biochemical interactions between NL1 and the NMDAR GluN1 subunit. Our work uncovers NL1 isoform-specific cisinteractions with ionotropic glutamate receptors as a key mechanism for controlling synaptic properties.synapse | neurotranmitter receptor | neurexin N MDA receptors (NMDARs) are key regulators of the development of neural circuits and synaptic plasticity (1, 2). In humans, perturbation of NMDAR function results in psychotic conditions, and genetic animal models with altered NMDAR activity exhibit phenotypes related to cognitive disorders such as schizophrenia and autism (3-5). Activity-dependent recruitment of NMDARs to synapses controls certain forms of synaptic plasticity (6, 7). However, the molecular mechanisms underlying the recruitment and physical tethering of NMDAR complexes at synapses are incompletely understood.Neuroligin-1 (NL1), one of four postsynaptic neuroligin adhesion molecules (NL1, 2, 3, 4), contributes to NMDAR regulation (8, 9). In cultured neurons, overexpression of NL1 promotes clustering of synaptic NMDARs (8), and NL1 KO mice show decreases in NMDAR-dependent excitatory postsynaptic currents (NMDAR EPSCs) (9-11). A major question in understanding neuroligin function is how specific isoforms couple to specific neurotransmitter receptors (12, 13). NMDARs were recovered in coimmunoprecipitations with NL proteins, indicating a potential complex formation, although in those experiments, no NL isoform-specificity was apparent (14). One candidate link between NLs and glutamate receptors is through postsynaptic scaffolding molecules such as postsynaptic density 95 (PSD95) (15, 16). However, all NL isoforms contain PSD95 binding sites, and NMDARs and PSD95 were recruited to NL1 with different time courses (14).Our results demonstrate that NL1 controls synaptic abundance of NMDAR via NL1-specific extracellular determinants. Loss of these interactions results in impairment of NMDAR-mediated transmission and synaptic plasticity. Our findings uncover an unexpected mode of NL1-NMDAR coupling and demonstrate a key role for the NL1 adhesion protein in the physical incorporation and retention of NMDAR at glutamatergic synapses.Results NL1-Specific Recruitment of NMDARs Does Not Require PSD95. We examined the specificity of molecular coupling of NL isoforms (NL1, 2, 3) to NMDARs by NL overexpression in cultured hippocampal neurons. NL1 increased the density of clusters of the NMDAR subunits GluN1, GluN2A, and GluN...

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“…The nearly normal neurological function of Nlgn3 knockout mice 3–5 is attributed to compensatory expression of other neuroligins 2,6 . We found no effect of NLGN1, NLGN4X/Y (Extended Data Fig.…”

mentioning

confidence: 99%

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Venkatesh

Tam

Woo

et al. 2017

Nature

371

374

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Summary High-grade gliomas (HGG) are a devastating group of cancers, representing the leading cause of brain tumor-related death in both children and adults. Therapies aimed at mechanisms intrinsic to the glioma cell have translated to only limited success; effective therapeutic strategies will need to also target elements of the tumor microenvironment that promote glioma progression. We recently demonstrated that neuronal activity robustly promotes the growth of a range of molecularly and clinically distinct HGG types, including adult glioblastoma (GBM), anaplastic oligodendroglioma, pediatric GBM, and diffuse intrinsic pontine glioma (DIPG)1. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway1. However, neuroligin-3 necessity to glioma growth, proteolytic mechanism of secretion and further molecular consequences in glioma remain to be clarified. Here, we demonstrate a striking dependence of HGG growth on microenvironmental neuroligin-3, elucidate signaling cascades downstream of neuroligin-3 binding in glioma and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. Neuroligin-3 stimulates numerous oncogenic pathways, including early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes including upregulation of numerous synapse-related genes in glioma cells. Neuroligin-3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent release of neuroligin-3 into the tumor microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting neuroligin-3 secretion, which could prove transformative for HGG therapy.

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Neuroligin-1 Deletion Results in Impaired Spatial Memory and Increased Repetitive Behavior

Cited by 396 publications

References 76 publications

Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

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