Original Article

Transcriptome alterations of prefrontal cortical parvalbumin neurons in schizophrenia

Received:
Revised:
Accepted:
Published:

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.

  • Subscribe to Molecular Psychiatry for full access:

    $636

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    , . Schizophrenia is a cognitive illness: time for a change in focus. JAMA Psychiatry 2013; 70: 1107–1112.

  2. 2.

    , . Schizophrenia as a disorder of molecular pathways. Biol Psychiatry 2015; 77: 22–28.

  3. 3.

    , . Progress in the use of microarray technology to study the neurobiology of disease. Nat Neurosci 2004; 7: 434–439.

  4. 4.

    , , , , , et al. Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder. Mol Psychiatry 2015; 20: 1397–1405.

  5. 5.

    , . Molecular influences on working memory circuits in dorsolateral prefrontal cortex. Prog Mol Biol Transl Sci 2014; 122: 211–231.

  6. 6.

    , . Cortical basket cell dysfunction in schizophrenia. J Physiol 2012; 590(Pt 4): 715–724.

  7. 7.

    , , . Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia. Front Behav Neurosci 2013; 7: 116.

  8. 8.

    , , . Impaired GABAergic neurotransmission in schizophrenia underlies impairments in cortical gamma band oscillations. Curr Psychiatry Rep 2013; 15: 346.

  9. 9.

    , , , , , et al. Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 2008; 13: 147–161.

  10. 10.

    , , , , , . Reduced labeling of parvalbumin neurons and perineuronal nets in the dorsolateral prefrontal cortex of subjects with schizophrenia. Neuropsychopharmacology 2016; 41: 2206–2214.

  11. 11.

    , , . Altered parvalbumin basket cell inputs in the dorsolateral prefrontal cortex of schizophrenia subjects. Mol Psychiatry 2014; 19: 30–36.

  12. 12.

    , , , , , 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.

  13. 13.

    , , , , , 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.

  14. 14.

    , , , , , 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.

  15. 15.

    , , . 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.

  16. 16.

    , , , . 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.

  17. 17.

    , , . Activity-dependent changes in GAD and preprotachykinin mRNAs in visual cortex of adult monkeys. Cereb Cortex 1994; 4: 40–51.

  18. 18.

    , , , , , . 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.

  19. 19.

    , . Dendritic spine pathology in schizophrenia. Neuroscience 2013; 251: 90–107.

  20. 20.

    , , , , , . Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia. Am J Psychiatry 2010; 167: 1479–1488.

  21. 21.

    , , . Wisteria floribunda agglutinin-labelled nets surround parvalbumin-containing neurons. Neuroreport 1992; 3: 869–872.

  22. 22.

    , , , , . 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.

  23. 23.

    , , , , . 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.

  24. 24.

    , . The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 1986; 51: 1173–1182.

  25. 25.

    . A direct approach to false discovery rates. J Roy Stat Soc B 2002; 64: 479–498.

  26. 26.

    , , , , . 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.

  27. 27.

    , , , , , et al. Molecular and genetic characterization of depression: overlap with other psychiatric disorders and aging. Mol Neuropsychiatry 2015; 1: 1–12.

  28. 28.

    , , , , , . Altered cortical expression of GABA-related genes in schizophrenia: illness progression vs developmental disturbance. Schizophr Bull 2015; 41: 180–191.

  29. 29.

    , , , , , 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.

  30. 30.

    , , , . Dysregulation of glucocorticoid receptor co-factors FKBP5, BAG1 and PTGES3 in prefrontal cortex in psychotic illness. Sci Rep 2013; 3: 3539.

  31. 31.

    , , . Altered gene expression in the superior temporal gyrus in schizophrenia. BMC Genomics 2008; 9: 199.

  32. 32.

    , . Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder. Neuropsychopharmacology 2008; 33: 2175–2186.

  33. 33.

    , , , , , 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.

  34. 34.

    , . Balancing plasticity/stability across brain development. Prog Brain Res 2013; 207: 3–34.

  35. 35.

    , , , , . 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.

  36. 36.

    , , , , , et al. Abnormal expression of cell recognition molecules in schizophrenia. Exp Neurol 1998; 149: 424–432.

  37. 37.

    , , , , , . Transcriptome alterations in prefrontal pyramidal cells distinguish schizophrenia from bipolar and major depressive disorders. Biol Psychiatry 2017; 82: 594–600.

  38. 38.

    , , , . Altered markers of cortical gamma-aminobutyric acid neuronal activity in schizophrenia: role of the NARP gene. JAMA Psychiatry 2015; 72: 747–756.

  39. 39.

    , , , , , . Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia. Am J Psychiatry 2008; 165: 479–489.

  40. 40.

    , , , , , et al. Molecular profiles of parvalbumin-immunoreactive neurons in the superior temporal cortex in schizophrenia. J Neurogenet 2014; 28: 70–85.

  41. 41.

    , , , . Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert. Brain Res Mol Brain Res 2002; 107: 183–189.

  42. 42.

    , , , , , et al. Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia. Biol Psychiatry 2013; 74: 427–435.

  43. 43.

    , , . Targeting oxidative stress and aberrant critical period plasticity in the developmental trajectory to schizophrenia. Schizophr Bull 2015; 41: 835–846.

  44. 44.

    , , . Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning. Nature 2013; 504: 272–276.

  45. 45.

    , , , . Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci 2012; 35: 57–67.

  46. 46.

    , , , , , et al. Redox dysregulation in schizophrenia revealed by in vivo NAD+/NADH measurement. Schizophr Bull 2016; 43: 197–204.

  47. 47.

    , , , , , et al. Energy deficit in parvalbumin neurons leads to circuit dysfunction, impaired sensory gating and social disability. Neurobiol Dis 2016; 93: 35–46.

  48. 48.

    , , , , , et al. Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts. Biol Psychiatry 2005; 58: 85–96.

  49. 49.

    , , , , . Transcriptome alterations of mitochondrial and coagulation function in schizophrenia by cortical sequencing analysis. BMC Genomics 2014; 15(Suppl 9): S6.

  50. 50.

    , , , , , et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet 2008; 40: 751–760.

  51. 51.

    , , . Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry 2015; 77: 1031–1040.

  52. 52.

    , . Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 2000; 57: 65–73.

  53. 53.

    , , , . Prefrontal cortical dendritic spine pathology in schizophrenia and bipolar disorder. JAMA Psychiatry 2014; 71: 1323–1331.

  54. 54.

    , , , , , et al. Reduced protein synthesis in schizophrenia patient-derived olfactory cells. Transl Psychiatry 2015; 5: e663.

  55. 55.

    , , , . Synaptic targets of pyramidal neurons providing intrinsic horizontal connections in monkey prefrontal cortex. J Comp Neurol 1998; 390: 211–224.

  56. 56.

    , , , , , . Dysregulated ErbB4 splicing in schizophrenia: selective effects on parvalbumin expression. Am J Psychiatry 2015; 173: 60–68.

Download references

Acknowledgements

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

Author notes

    • J P Corradi

    Current address: Hartford Hospital, Hartford, CT, USA.

Affiliations

  1. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    • J F Enwright III
    • , D Arion
    •  & D A Lewis
  2. Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA

    • Z Huo
    •  & G Tseng
  3. Bristol-Myers Squib, Wallingford, CT, USA

    • J P Corradi
  4. Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

    • D A Lewis

Authors

  1. Search for J F Enwright III in:

  2. Search for Z Huo in:

  3. Search for D Arion in:

  4. Search for J P Corradi in:

  5. Search for G Tseng in:

  6. Search for D A Lewis in:

Competing interests

David A. Lewis currently receives investigator-initiated research support from Pfizer. All other authors declare no conflicts of interest.

Corresponding author

Correspondence to D A Lewis.

Supplementary information

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)