The NOS1 variant rs6490121 is associated with variation in prefrontal function and grey matter density in healthy individuals

A common polymorphism within the nitric oxide sythanse-1 (NOS1) gene (rs6490121), initially identified as risk variant for schizophrenia, has been associated with variation in working memory and IQ. Here we investigated how this variation might be mediated at the level of brain structure and function. In healthy individuals (N=157), voxel based morphometry was used to compare grey matter (GM) volume between homozygous and heterozygous carriers of the 'G' allele (i.e. the allele associated with impaired cognition and schizophrenia risk) and homozygous carriers of the non-risk 'A' allele. Functional brain imaging data were also acquired from 48 participants during performance of a spatial working memory (SWM) task, and analysed to determine any effect of NOS1 risk status. An a priori region-of-interest analysis identified a significant reduction in ventromedial prefrontal GM volume in 'G' allele carriers. Risk carriers also exhibited altered patterns of activation in the prefrontal cortex, caudate, and superior parietal lobe, which were characteristic of abnormal increases in activation in frontoparietal working memory networks and a failure to disengage regions of the default mode network. These functional changes suggest a NOS1-mediated processing inefficiency, which may contribute to cognitive dysfunction in schizophrenia. While the mechanisms by which NOS1 may influence brain structure and/or function have not yet been well delineated, these data provide further evidence for a role of NOS1 in risk for schizophrenia via an impact upon cognitive function.

[1]  Ann-Christine Ehlis,et al.  A functional promoter polymorphism of neuronal nitric oxide synthase moderates prefrontal functioning in schizophrenia. , 2011, The international journal of neuropsychopharmacology.

[2]  Lin He,et al.  Evidence for association between the 5' flank of the NOS1 gene and schizophrenia in the Chinese population. , 2008, The international journal of neuropsychopharmacology.

[3]  Marika Paaver,et al.  A functional NOS1 promoter polymorphism interacts with adverse environment on functional and dysfunctional impulsivity , 2011, Psychopharmacology.

[4]  John Stewart,et al.  A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder. , 2002, The American journal of psychiatry.

[5]  C. Chiueh,et al.  Neurobiology of NO· and ·OH: Basic Research and Clinical Relevance , 1994, Annals of the New York Academy of Sciences.

[6]  C. Spencer,et al.  Identification of loci associated with schizophrenia by genome-wide association and follow-up , 2008, Nature Genetics.

[7]  D Saur,et al.  A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function , 2006, Molecular Psychiatry.

[8]  Mario Engelmann,et al.  Impaired cognitive performance in neuronal nitric oxide synthase knockout mice is associated with hippocampal protein derangements. , 2004, Nitric oxide : biology and chemistry.

[9]  J. Binder,et al.  A Parametric Manipulation of Factors Affecting Task-induced Deactivation in Functional Neuroimaging , 2003, Journal of Cognitive Neuroscience.

[10]  N. Toda,et al.  Cerebral blood flow regulation by nitric oxide in neurological disorders. , 2009, Canadian journal of physiology and pharmacology.

[11]  A. Gürel,et al.  Nitric oxide as a physiopathological factor in neuropsychiatric disorders. , 2004, In vivo.

[12]  Tim Hahn,et al.  NOS1 ex1f‐VNTR polymorphism affects prefrontal oxygenation during response inhibition tasks , 2012, Human brain mapping.

[13]  Nicolas Singewald,et al.  Nitric oxide modulates the release of serotonin in the rat hypothalamus , 1999, Brain Research.

[14]  R. Huganir,et al.  Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. , 2005, American journal of human genetics.

[15]  T. Paus,et al.  Functional coactivation map of the human brain. , 2008, Cerebral cortex.

[16]  Danielle S Bassett,et al.  Cognitive fitness of cost-efficient brain functional networks , 2009, Proceedings of the National Academy of Sciences.

[17]  Jörgen A. Engel,et al.  Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms , 2004, Psychopharmacology.

[18]  J. Engel,et al.  The neuronal selective nitric oxide synthase inhibitor, Nomega-propyl-L-arginine, blocks the effects of phencyclidine on prepulse inhibition and locomotor activity in mice. , 2004, European journal of pharmacology.

[19]  Ian J. Deary,et al.  Association of Existing and New Candidate Genes for Anxiety, Depression and Personality Traits in Older People , 2010, Behavior genetics.

[20]  G. Wogan,et al.  Nitric oxide as a modulator of apoptosis. , 2005, Cancer letters.

[21]  C. Chiueh,et al.  Neuroprotective Properties of Nitric Oxide , 1999, Annals of the New York Academy of Sciences.

[22]  Bernhard Bogerts,et al.  The many faces of nitric oxide in schizophrenia. A review , 2005, Schizophrenia Research.

[23]  John G. Csernansky,et al.  Neurodegeneration in Schizophrenia: Evidence from In Vivo Neuroimaging Studies , 2007, TheScientificWorldJournal.

[24]  Karl J. Friston,et al.  Voxel-Based Morphometry—The Methods , 2000, NeuroImage.

[25]  Shih-Jen Tsai,et al.  Association analysis for the CA repeat polymorphism of the neuronal nitric oxide synthase (NOS1) gene and schizophrenia , 2003, Schizophrenia Research.

[26]  G L Shulman,et al.  INAUGURAL ARTICLE by a Recently Elected Academy Member:A default mode of brain function , 2001 .

[27]  Paul J. Laurienti,et al.  An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets , 2003, NeuroImage.

[28]  Pall I. Olason,et al.  Common variants conferring risk of schizophrenia , 2009, Nature.

[29]  G. Shulman,et al.  Medial prefrontal cortex and self-referential mental activity: Relation to a default mode of brain function , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Joseph H Callicott,et al.  Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls. , 2010, Archives of general psychiatry.

[31]  Guy C. Brown,et al.  Nitric oxide and neuronal death. , 2010, Nitric oxide : biology and chemistry.

[32]  John Ashburner,et al.  A fast diffeomorphic image registration algorithm , 2007, NeuroImage.

[33]  D. Lorrain,et al.  Nitric oxide increases dopamine and serotonin release in the medial preoptic area , 1993, Neuroreport.

[34]  Jörgen A. Engel,et al.  The nitric oxide synthase inhibitor, L-NAME, blocks phencyclidine-induced disruption of prepulse inhibition in mice , 2001, Psychopharmacology.

[35]  D. Schacter,et al.  The Brain's Default Network , 2008, Annals of the New York Academy of Sciences.

[36]  T. Shinkai,et al.  Allelic association of the neuronal nitric oxide synthase (NOS1) gene with schizophrenia , 2002, Molecular Psychiatry.

[37]  D. Jackson,et al.  Nitric oxide synthase inhibition blocks phencyclidine-induced behavioural effects on prepulse inhibition and locomotor activity in the rat , 1997, Psychopharmacology.

[38]  Ann-Christine Ehlis,et al.  Influence of functional variant of neuronal nitric oxide synthase on impulsive behaviors in humans. , 2009, Archives of general psychiatry.

[39]  Jörgen A. Engel,et al.  The nitric oxide synthase inhibitor. L-NAME, blocks certain phencyclidine-induced but not amphetamine-induced effects on behaviour and brain biochemistry in the rat , 1998, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[40]  D. Bredt,et al.  Synaptic signaling by nitric oxide , 1997, Current Opinion in Neurobiology.

[41]  R. Turner,et al.  Does Hypercapnia-Induced Cerebral Vasodilation Modulate the Hemodynamic Response to Neural Activation? , 2001, NeuroImage.

[42]  Kim Fejgin,et al.  The amino acid l-lysine blocks the disruptive effect of phencyclidine on prepulse inhibition in mice , 2007, Psychopharmacology.

[43]  R W Cox,et al.  AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. , 1996, Computers and biomedical research, an international journal.

[44]  Trevor Archer,et al.  Effects of phencyclidine on spatial learning and memory: Nitric oxide-dependent mechanisms , 2006, Behavioural Brain Research.

[45]  Maurizio Corbetta,et al.  The human brain is intrinsically organized into dynamic, anticorrelated functional networks. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Mario Engelmann,et al.  Neuronal nitric oxide synthase knock-out mice show impaired cognitive performance. , 2004, Nitric oxide : biology and chemistry.

[47]  Russell J. Andrews,et al.  Neuroprotective agents : seventh international conference , 1997 .

[48]  Hidenao Fukuyama,et al.  Brain volume and dysexecutive behavior in schizophrenia , 2009, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[49]  E. Oldfield,et al.  Effects of Nitric Oxide on Reactive Oxygen Species Production and Infarction Size after Brain Reperfusion Injury , 2001, Neurosurgery.

[50]  Michael Gill,et al.  Influence of NOS1 on verbal intelligence and working memory in both patients with schizophrenia and healthy control subjects. , 2009, Archives of general psychiatry.

[51]  K. Kuriyama,et al.  Nitric oxide-evoked [3H] gamma-aminobutyric acid release is mediated by two distinct release mechanisms. , 1996, Brain research. Molecular brain research.

[52]  M. Bullock,et al.  The Significance of Nitric Oxide Production in the Brain After Injury , 2002, Annals of the New York Academy of Sciences.

[53]  Alan C. Evans,et al.  Detecting changes in nonisotropic images , 1999, Human brain mapping.

[54]  D. Butterfield,et al.  Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity , 2007, Nature Reviews Neuroscience.

[55]  Jörgen A. Engel,et al.  Effects of phencyclidine on acoustic startle and prepulse inhibition in neuronal nitric oxide synthase deficient mice , 2005, European Neuropsychopharmacology.

[56]  N. Toda,et al.  Control of systemic and pulmonary blood pressure by nitric oxide formed through neuronal nitric oxide synthase , 2009, Journal of hypertension.

[58]  Ernesto Fedele,et al.  The NOS/sGC pathway in the rat central nervous system: a microdialysis overview , 2004, Neurochemistry International.

[59]  S. Snyder,et al.  Novel neural modulators. , 2003, Annual review of neuroscience.

[60]  J. Garthwaite,et al.  Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain , 1988, Nature.

[61]  J. Callicott,et al.  Dysfunctional and compensatory prefrontal cortical systems, genes and the pathogenesis of schizophrenia. , 2007, Cerebral cortex.

[62]  Thomas Dresler,et al.  NOS1 ex1f-VNTR polymorphism influences prefrontal brain oxygenation during a working memory task , 2011, NeuroImage.

[63]  John J. Foxe,et al.  A NOS1 variant implicated in cognitive performance influences evoked neural responses during a high density EEG study of early visual perception , 2012, Human brain mapping.

[64]  P. Marsden,et al.  Structural organization of the human neuronal nitric oxide synthase gene (NOS1). , 1994, The Journal of biological chemistry.

[65]  Thomas E. Nichols,et al.  Nonstationary cluster-size inference with random field and permutation methods , 2004, NeuroImage.

[66]  D. Joel,et al.  The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum , 2000, Neuroscience.

[67]  K. Johnson,et al.  Nitric oxide induces neurotransmitter release from hippocampal slices. , 1992, European journal of pharmacology.

[68]  S. Siris,et al.  Implications of normal brain development for the pathogenesis of schizophrenia. , 1988, Archives of general psychiatry.

[69]  Jakob Korf,et al.  NEUROBIOLOGY OF NO- AND -OH , 1994 .

[70]  Federica Buonocore,et al.  Effects of cis-regulatory variation differ across regions of the adult human brain. , 2010, Human molecular genetics.