title: Prefrontal White Matter Structure Mediates the Influence of GAD1 on Working Memory.
abstract: The glutamic acid decarboxylase 1 (GAD1) gene is a major determinant of γ-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter modulating local neuronal circuitry. GABAergic dysfunction and expression of GAD1 have been implicated in the pathophysiology of schizophrenia, and in working memory impairment. We examined the influence of the functional GAD1 rs3749034 variant on white matter fractional anisotropy (FA), cortical thickness, and working memory performance in schizophrenia patients and healthy controls (N=197). Using transcranial magnetic stimulation with electroencephalography (TMS-EEG), we subsequently examined the effect of rs3749034 on long-interval cortical inhibition (LICI) in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia patients and healthy controls (N=66). We found that the rs3749034 T-allele carrier risk group had lower voxel-wise FA in the prefrontal cortex region (PFWE-corrected<0.05) but not cortical thickness. Mixed-model regression revealed a significant effect on attentional processing and working memory across four performance measures (F1,182=11.5, P=8 × 10(-4)). FA in the prefrontal cortex was associated with digit-span performance. Voxel-wise mediation analysis revealed that the effect GAD1 on poorer digit-span performance statistically predicted the lower white matter FA (PFWE-corrected<0.05). In exploratory analysis, we found a prominent GAD1 genotype-by-diagnosis interaction on DLPFC LICI (F1,56=14.3, P=4.1 × 10(-4)). Our findings converge on variation in GAD1 gene predicting a susceptibility mechanism that affects white matter FA, GABAergic inhibitory neurotransmission in the DLPFC, and working memory performance. Furthermore, via voxel mediation of FA and TMS-EEG intervention, we provide evidence for a potentially causal mechanism through which aberrant DLPFC GABA signaling may contribute to working memory dysfunction.
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin, Berlin, Germany.|Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Tristram A
authors.initials: TA
authors.lastname: Lett
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Radhu
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Luis G
authors.initials: LG
authors.lastname: Dominguez
authors.affiliation: Cerebral Imaging Centre, Douglas Hospital Mental Health University Institute, Verdun, QC, Canada.|Departments of Psychiatry and Biomedical Engineering, McGill University, Montreal, QC, Canada.
authors.forename: M Mallar
authors.initials: MM
authors.lastname: Chakravarty
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Arash
authors.initials: A
authors.lastname: Nazeri
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Faranak
authors.initials: F
authors.lastname: Farzan
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Walter
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Benoit H
authors.initials: BH
authors.lastname: Mulsant
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Zafiris J
authors.initials: ZJ
authors.lastname: Daskalakis
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Aristotle N
authors.initials: AN
authors.lastname: Voineskos
mesh_terms: D000328:Adult; D038524:Diffusion Magnetic Resonance Imaging; D004569:Electroencephalography; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008570:Memory, Short-Term; D008875:Middle Aged; D009433:Neural Inhibition; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000473:pathology*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D012565:Schizophrenic Psychology; D050781:Transcranial Magnetic Stimulation; D066127:White Matter / Q000000981:diagnostic imaging / Q000473:pathology*
chemical_list: D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
references.citation: Neuropharmacology. 1999 Nov;38(11):1755-66
references.pmid: 10587091
references.citation: Nat Neurosci. 2000 Mar;3(3):284-91
references.pmid: 10700262
references.citation: Clin Neurophysiol. 2001 Apr;112(4):720
references.pmid: 11332408
references.citation: Nat Neurosci. 2001 Dec;4(12):1253-8
references.pmid: 11694885
references.citation: J Psychiatr Res. 1975 Nov;12(3):189-98
references.pmid: 1202204
references.citation: Nature. 2003 Dec 18;426(6968):789-96
references.pmid: 14685227
references.citation: Biol Psychiatry. 2005 Feb 1;57(3):252-60
references.pmid: 15691526
references.citation: Nat Rev Neurosci. 2005 Mar;6(3):215-29
references.pmid: 15738957
references.citation: Nat Rev Neurosci. 2005 Apr;6(4):312-24
references.pmid: 15803162
references.citation: Psychiatry Res. 1992 Mar;41(3):237-48
references.pmid: 1594710
references.citation: Biol Psychiatry. 2005 Dec 15;58(12):930-6
references.pmid: 16112657
references.citation: Exp Brain Res. 2006 Aug;173(1):86-93
references.pmid: 16489434
references.citation: J Neurochem. 2006 Apr;97(2):385-96
references.pmid: 16539672
references.citation: Exp Brain Res. 2006 Oct;174(3):403-12
references.pmid: 16683138
references.citation: J Neurosci Methods. 2007 Aug 15;164(1):177-90
references.pmid: 17517438
references.citation: Mol Psychiatry. 2007 Sep;12(9):854-69
references.pmid: 17767149
references.citation: Arch Gen Psychiatry. 2007 Nov;64(11):1242-50
references.pmid: 17984393
references.citation: Trends Neurosci. 2008 May;31(5):234-42
references.pmid: 18395805
references.citation: Clin EEG Neurosci. 2008 Jul;39(3):150-5
references.pmid: 18751565
references.citation: Clin Neurophysiol. 2009 Dec;120(12):2008-2039
references.pmid: 19833552
references.citation: Nat Rev Neurosci. 2010 Feb;11(2):100-13
references.pmid: 20087360
references.citation: Neurobiol Aging. 2012 Jan;33(1):21-34
references.pmid: 20363050
references.citation: Neuropsychopharmacology. 2010 Aug;35(9):1943-51
references.pmid: 20463658
references.citation: Nat Rev Neurosci. 2011 Apr;12(4):231-42
references.pmid: 21407245
references.citation: Biol Psychiatry. 2011 Jul 1;70(1):19-27
references.pmid: 21571254
references.citation: J Physiol. 2011 Sep 15;589(Pt 18):4423-35
references.pmid: 21768267
references.citation: J Neurosci. 2011 Jul 27;31(30):11088-95
references.pmid: 21795557
references.citation: Trends Neurosci. 2012 Jan;35(1):57-67
references.pmid: 22154068
references.citation: J Affect Disord. 2012 Feb;136(3):249-57
references.pmid: 22217432
references.citation: Restor Neurol Neurosci. 2012;30(2):103-13
references.pmid: 22233802
references.citation: Cereb Cortex. 2013 Mar;23(3):552-9
references.pmid: 22368081
references.citation: Neuroscientist. 2012 Oct;18(5):467-86
references.pmid: 22547529
references.citation: Cortex. 2013 May;49(5):1377-85
references.pmid: 22795183
references.citation: Biol Psychiatry. 2013 Mar 15;73(6):510-7
references.pmid: 23039931
references.citation: J Psychiatr Res. 2013 Jul;47(7):872-9
references.pmid: 23566421
references.citation: Biol Psychiatry. 2014 Mar 1;75(5):361-70
references.pmid: 24011822
references.citation: Cereb Cortex. 2015 May;25(5):1290-6
references.pmid: 24275833
references.citation: PLoS One. 2014 Mar 18;9(3):e92354
references.pmid: 24642981
references.citation: Neuroimage. 2014 Jul 15;95:136-50
references.pmid: 24657781
references.citation: Nature. 2014 Jul 24;511(7510):421-7
references.pmid: 25056061
references.citation: Biol Psychiatry. 2015 Oct 15;78(8):582-9
references.pmid: 25444169
references.citation: Cortex. 2015 Mar;64:68-77
references.pmid: 25461708
references.citation: Brain. 2015 Feb;138(Pt 2):483-97
references.pmid: 25524710
references.citation: Cereb Cortex. 1995 Nov-Dec;5(6):550-60
references.pmid: 8590827