Complexin2 modulates working memory-related neural activity in patients with schizophrenia

  • Johanna Hass
  • Esther Walton
  • Holger Kirsten
  • Jessica Turner
  • Rick Wolthusen
  • Veit Roessner
  • Scott R. Sponheim
  • Daphne Holt
  • Randy Gollub
  • Vince D. Calhoun
  • Stefan EhrlichEmail author
Original Paper


The specific contribution of risk or candidate gene variants to the complex phenotype of schizophrenia is largely unknown. Studying the effects of such variants on brain function can provide insight into disease-associated mechanisms on a neural systems level. Previous studies found common variants in the complexin2 (CPLX2) gene to be highly associated with cognitive dysfunction in schizophrenia patients. Similarly, cognitive functioning was found to be impaired in Cplx2 gene-deficient mice if they were subjected to maternal deprivation or mild brain trauma during puberty. Here, we aimed to study seven common CPLX2 single-nucleotide polymorphisms (SNPs) and their neurogenetic risk mechanisms by investigating their relationship to a schizophrenia-related functional neuroimaging intermediate phenotype. We examined functional MRI and genotype data collected from 104 patients with DSM-IV-diagnosed schizophrenia and 122 healthy controls who participated in the Mind Clinical Imaging Consortium study of schizophrenia. Seven SNPs distributed over the whole CPLX2 gene were tested for association with working memory-elicited neural activity in a frontoparietal neural network. Three CPLX2 SNPs were significantly associated with increased neural activity in the dorsolateral prefrontal cortex and intraparietal sulcus in the schizophrenia sample, but showed no association in healthy controls. Since increased working memory-related neural activity in individuals with or at risk for schizophrenia has been interpreted as ‘neural inefficiency,’ these findings suggest that certain variants of CPLX2 may contribute to impaired brain function in schizophrenia, possibly combined with other deleterious genetic variants, adverse environmental events, or developmental insults.


Complexin2 Imaging genetics Intermediate phenotype Working memory Frontoparietal circuit Schizophrenia 



This work was supported by the National Institutes of Health (NIH/NCRR P41RR14075), Department of Energy (DE-FG02-99ER62764), MIND Research Network, Morphometry BIRN (1U24, RR021382A), Function BIRN (U24RR021992-01, NIH.NCRR MO1 RR025758-01), NARSAD Young Investigator Grant (SE), and the Deutsche Forschungsgemeinschaft (Research Fellowship to SE).

Conflict of interest

Veit Roessner has received lecture fees from Eli Lilly, Janssen-Cilag, Medice, and Novartis and was a member of advisory boards of Eli Lilly and Novartis. All other authors declare that they have no conflicts of interest.

Supplementary material

406_2014_550_MOESM1_ESM.pdf (411 kb)
Supplementary material 1 (PDF 411 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Johanna Hass
    • 1
  • Esther Walton
    • 1
  • Holger Kirsten
    • 2
    • 3
  • Jessica Turner
    • 4
  • Rick Wolthusen
    • 1
    • 6
    • 7
  • Veit Roessner
    • 1
  • Scott R. Sponheim
    • 5
  • Daphne Holt
    • 6
    • 7
  • Randy Gollub
    • 6
    • 7
  • Vince D. Calhoun
    • 4
    • 8
  • Stefan Ehrlich
    • 1
    • 6
    • 7
    Email author
  1. 1.Department of Child and Adolescent PsychiatryFaculty of Medicine Carl Gustav Carus of the Technische Universität DresdenDresdenGermany
  2. 2.Institute for Medical Informatics, Statistics and Epidemiology (IMISE)University of LeipzigLeipzigGermany
  3. 3.LIFE (Leipzig Interdisciplinary Research Cluster of Genetic Factors, Phenotypes and Environment)University of LeipzigLeipzigGermany
  4. 4.The MIND Research NetworkAlbuquerqueUSA
  5. 5.Department of Psychiatry, Center for Magnetic Resonance ResearchUniversity of MinnesotaMinneapolisUSA
  6. 6.MGH/MIT/HMS Martinos Center for Biomedical ImagingMassachusetts General HospitalCharlestownUSA
  7. 7.Department of PsychiatryMassachusetts General HospitalBostonUSA
  8. 8.Department of Electrical and Computer EngineeringUniversity of New MexicoAlbuquerqueUSA

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