Abstract
Schizophrenia (SZ) is associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction is manifest as cognitive deficits that appear to arise from disturbances in gamma frequency oscillations. These oscillations are generated in DLPFC layer 3 (L3) via reciprocal connections between pyramidal cells (PCs) and parvalbumin (PV)-containing interneurons. The density of cortical PV neurons is not altered in SZ, but expression levels of several transcripts involved in PV cell function, including PV, are lower in the disease. However, the transcriptome of PV cells has not been comprehensively assessed in a large cohort of subjects with SZ. In this study, we combined an immunohistochemical approach, laser microdissection, and microarray profiling to analyze the transcriptome of DLPFC L3 PV cells in 36 matched pairs of SZ and unaffected comparison subjects. Over 800 transcripts in PV neurons were identified as differentially expressed in SZ subjects; most of these alterations have not previously been reported. The altered transcripts were enriched for pathways involved in mitochondrial function and tight junction signaling. Comparison with the transcriptome of L3 PCs from the same subjects revealed both shared and distinct disease-related effects on gene expression between cell types. Furthermore, network structures of gene pathways differed across cell types and subject groups. These findings provide new insights into cell type-specific molecular alterations in SZ which may point toward novel strategies for identifying therapeutic targets.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kahn RS, Keefe RS. Schizophrenia is a cognitive illness: time for a change in focus. JAMA Psychiatry 2013; 70: 1107–1112.
Horvath S, Mirnics K. Schizophrenia as a disorder of molecular pathways. Biol Psychiatry 2015; 77: 22–28.
Mirnics K, Pevsner J. Progress in the use of microarray technology to study the neurobiology of disease. Nat Neurosci 2004; 7: 434–439.
Arion D, Corradi JP, Tang S, Datta D, Boothe F, He A et al. Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder. Mol Psychiatry 2015; 20: 1397–1405.
Arnsten AF, Jin LE. Molecular influences on working memory circuits in dorsolateral prefrontal cortex. Prog Mol Biol Transl Sci 2014; 122: 211–231.
Curley AA, Lewis DA. Cortical basket cell dysfunction in schizophrenia. J Physiol 2012; 590(Pt 4): 715–724.
Jiang Z, Cowell RM, Nakazawa K. Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia. Front Behav Neurosci 2013; 7: 116.
McNally JM, McCarley RW, Brown RE. Impaired GABAergic neurotransmission in schizophrenia underlies impairments in cortical gamma band oscillations. Curr Psychiatry Rep 2013; 15: 346.
Hashimoto T, Arion D, Unger T, Maldonado-Aviles JG, Morris HM, Volk DW et al. Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 2008; 13: 147–161.
Enwright JF, Sanapala S, Foglio A, Berry R, Fish KN, Lewis DA. Reduced labeling of parvalbumin neurons and perineuronal nets in the dorsolateral prefrontal cortex of subjects with schizophrenia. Neuropsychopharmacology 2016; 41: 2206–2214.
Glausier JR, Fish KN, Lewis DA. Altered parvalbumin basket cell inputs in the dorsolateral prefrontal cortex of schizophrenia subjects. Mol Psychiatry 2014; 19: 30–36.
Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 2003; 23: 6315–6326.
Georgiev D, Arion D, Enwright JF, Kikuchi M, Minabe Y, Corradi JP et al. Lower gene expression for KCNS3 potassium channel subunit in parvalbumin-containing neurons in the prefrontal cortex in schizophrenia. Am J Psychiatry 2014; 171: 62–71.
Perez-Santiago J, Diez-Alarcia R, Callado LF, Zhang JX, Chana G, White CH et al. A combined analysis of microarray gene expression studies of the human prefrontal cortex identifies genes implicated in schizophrenia. J Psychiatr Res 2012; 46: 1464–1474.
Kimoto S, Bazmi HH, Lewis DA. Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex in schizophrenia: contribution of altered regulation by Zif268. Am J Psychiatry 2014; 171: 969–978.
Luo Y, Lathia J, Mughal M, Mattson MP. SDF1alpha/CXCR4 signaling, via ERKs and the transcription factor Egr1, induces expression of a 67-kDa form of glutamic acid decarboxylase in embryonic hippocampal neurons. J Biol Chem 2008; 283: 24789–24800.
Benson DL, Huntsman MM, Jones EG. Activity-dependent changes in GAD and preprotachykinin mRNAs in visual cortex of adult monkeys. Cereb Cortex 1994; 4: 40–51.
Kinney JW, Davis CN, Tabarean I, Conti B, Bartfai T, Behrens MM. A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J Neurosci 2006; 26: 1604–1615.
Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience 2013; 251: 90–107.
Fung SJ, Webster MJ, Sivagnanasundaram S, Duncan C, Elashoff M, Weickert CS. Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia. Am J Psychiatry 2010; 167: 1479–1488.
Hartig W, Brauer K, Bruckner G. Wisteria floribunda agglutinin-labelled nets surround parvalbumin-containing neurons. Neuroreport 1992; 3: 869–872.
Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA. Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry 2000; 57: 237–245.
Wang X, Lin Y, Song C, Sibille E, Tseng GC. Detecting disease-associated genes with confounding variable adjustment and the impact on genomic meta-analysis: with application to major depressive disorder. BMCBioinformatics 2012; 13: 52.
Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 1986; 51: 1173–1182.
Storey JD. A direct approach to false discovery rates. J Roy Stat Soc B 2002; 64: 479–498.
Gaiteri C, Ding Y, French B, Tseng GC, Sibille E. Beyond modules and hubs: the potential of gene coexpression networks for investigating molecular mechanisms of complex brain disorders. Genes Brain Behav 2014; 13: 13–24.
Ding Y, Chang LC, Wang X, Guilloux JP, Parrish J, Oh H et al. Molecular and genetic characterization of depression: overlap with other psychiatric disorders and aging. Mol Neuropsychiatry 2015; 1: 1–12.
Hoftman GD, Volk DW, Bazmi HH, Li S, Sampson AR, Lewis DA. Altered cortical expression of GABA-related genes in schizophrenia: illness progression vs developmental disturbance. Schizophr Bull 2015; 41: 180–191.
Vawter MP, Shannon Weickert C, Ferran E, Matsumoto M, Overman K, Hyde TM et al. Gene expression of metabolic enzymes and a protease inhibitor in the prefrontal cortex are decreased in schizophrenia. Neurochem Res 2004; 29: 1245–1255.
Sinclair D, Fillman SG, Webster MJ, Weickert CS. Dysregulation of glucocorticoid receptor co-factors FKBP5, BAG1 and PTGES3 in prefrontal cortex in psychotic illness. Sci Rep 2013; 3: 3539.
Bowden NA, Scott RJ, Tooney PA. Altered gene expression in the superior temporal gyrus in schizophrenia. BMC Genomics 2008; 9: 199.
Beneyto M, Meador-Woodruff JH. Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder. Neuropsychopharmacology 2008; 33: 2175–2186.
MacDonald ML, Ding Y, Newman J, Hemby S, Penzes P, Lewis DA et al. Altered glutamate protein co-expression network topology linked to spine loss in the auditory cortex of schizophrenia. Biol Psychiatry 2015; 77: 959–968.
Takesian AE, Hensch TK. Balancing plasticity/stability across brain development. Prog Brain Res 2013; 207: 3–34.
Arion D, Unger T, Lewis DA, Levitt P, Mirnics K. Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia. Biol Psychiatry 2007; 62: 711–721.
Vawter MP, Cannon-Spoor HE, Hemperly JJ, Hyde TM, VanderPutten DM, Kleinman JE et al. Abnormal expression of cell recognition molecules in schizophrenia. Exp Neurol 1998; 149: 424–432.
Arion D, Huo Z, Enwright JF, Corradi JP, Tseng G, Lewis DA. Transcriptome alterations in prefrontal pyramidal cells distinguish schizophrenia from bipolar and major depressive disorders. Biol Psychiatry 2017; 82: 594–600.
Kimoto S, Zaki MM, Bazmi HH, Lewis DA. Altered markers of cortical gamma-aminobutyric acid neuronal activity in schizophrenia: role of the NARP gene. JAMA Psychiatry 2015; 72: 747–756.
Hashimoto T, Bazmi HH, Mirnics K, Wu Q, Sampson AR, Lewis DA. Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia. Am J Psychiatry 2008; 165: 479–489.
Pietersen CY, Mauney SA, Kim SS, Passeri E, Lim MP, Rooney RJ et al. Molecular profiles of parvalbumin-immunoreactive neurons in the superior temporal cortex in schizophrenia. J Neurogenet 2014; 28: 70–85.
Novak G, Kim D, Seeman P, Tallerico T. Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert. Brain Res Mol Brain Res 2002; 107: 183–189.
Mauney SA, Athanas KM, Pantazopoulos H, Shaskan N, Passeri E, Berretta S et al. Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia. Biol Psychiatry 2013; 74: 427–435.
Do KQ, Cuenod M, Hensch TK. Targeting oxidative stress and aberrant critical period plasticity in the developmental trajectory to schizophrenia. Schizophr Bull 2015; 41: 835–846.
Donato F, Rompani SB, Caroni P. Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning. Nature 2013; 504: 272–276.
Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci 2012; 35: 57–67.
Kim SY, Cohen BM, Chen X, Lukas SE, Shinn AK, Yuksel AC et al. Redox dysregulation in schizophrenia revealed by in vivo NAD+/NADH measurement. Schizophr Bull 2016; 43: 197–204.
Inan M, Zhao M, Manuszak M, Karakaya C, Rajadhyaksha AM, Pickel VM et al. Energy deficit in parvalbumin neurons leads to circuit dysfunction, impaired sensory gating and social disability. Neurobiol Dis 2016; 93: 35–46.
Altar CA, Jurata LW, Charles V, Lemire A, Liu P, Bukhman Y et al. Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts. Biol Psychiatry 2005; 58: 85–96.
Huang KC, Yang KC, Lin H, Tsao TT, Lee SA. Transcriptome alterations of mitochondrial and coagulation function in schizophrenia by cortical sequencing analysis. BMC Genomics 2014; 15(Suppl 9): S6.
Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet 2008; 40: 751–760.
Gonzalez-Burgos G, Cho RY, Lewis DA. Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry 2015; 77: 1031–1040.
Glantz LA, Lewis DA. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 2000; 57: 65–73.
Konopaske GT, Lange N, Coyle JT, Benes FM. Prefrontal cortical dendritic spine pathology in schizophrenia and bipolar disorder. JAMA Psychiatry 2014; 71: 1323–1331.
English JA, Fan Y, Focking M, Lopez LM, Hryniewiecka M, Wynne K et al. Reduced protein synthesis in schizophrenia patient-derived olfactory cells. Transl Psychiatry 2015; 5: e663.
Melchitzky DS, Sesack SR, Pucak ML, Lewis DA. Synaptic targets of pyramidal neurons providing intrinsic horizontal connections in monkey prefrontal cortex. J Comp Neurol 1998; 390: 211–224.
Chung DW, Volk DW, Arion D, Zhang Y, Sampson AR, Lewis DA. Dysregulated ErbB4 splicing in schizophrenia: selective effects on parvalbumin expression. Am J Psychiatry 2015; 173: 60–68.
Acknowledgments
We thank Carol Sue Johnston, Mary Ann Kelly, Kiley Laing, Kelly Rogers, Mary Brady and Jennifer Larsen for excellent technical assistance. This work was supported by National Institutes of Health Grants MH103204 and MH043784, and a grant from Bristol-Myers Squibb.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
David A. Lewis currently receives investigator-initiated research support from Pfizer. All other authors declare no conflicts of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Enwright III, J.F., Huo, Z., Arion, D. et al. Transcriptome alterations of prefrontal cortical parvalbumin neurons in schizophrenia. Mol Psychiatry 23, 1606–1613 (2018). https://doi.org/10.1038/mp.2017.216
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2017.216
This article is cited by
-
Effects of the mGlu2/3 receptor agonist LY379268 on two models of disturbed auditory evoked brain oscillations in mice
Translational Psychiatry (2023)
-
Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex
Genome Medicine (2022)
-
Expression of actin- and oxidative phosphorylation-related transcripts across the cortical visuospatial working memory network in unaffected comparison and schizophrenia subjects
Neuropsychopharmacology (2022)
-
Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia
Molecular Psychiatry (2022)
-
Schizophrenia: a disorder of broken brain bioenergetics
Molecular Psychiatry (2022)