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Impaired hippocampal–prefrontal synchrony in a genetic mouse model of schizophrenia

Abstract

Abnormalities in functional connectivity between brain areas have been postulated as an important pathophysiological mechanism underlying schizophrenia1,2. In particular, macroscopic measurements of brain activity in patients suggest that functional connectivity between the frontal and temporal lobes may be altered3,4. However, it remains unclear whether such dysconnectivity relates to the aetiology of the illness, and how it is manifested in the activity of neural circuits. Because schizophrenia has a strong genetic component5, animal models of genetic risk factors are likely to aid our understanding of the pathogenesis and pathophysiology of the disease. Here we study Df(16)A+/– mice, which model a microdeletion on human chromosome 22 (22q11.2) that constitutes one of the largest known genetic risk factors for schizophrenia6. To examine functional connectivity in these mice, we measured the synchronization of neural activity between the hippocampus and the prefrontal cortex during the performance of a task requiring working memory, which is one of the cognitive functions disrupted in the disease. In wild-type mice, hippocampal–prefrontal synchrony increased during working memory performance, consistent with previous reports in rats7. Df(16)A+/– mice, which are impaired in the acquisition of the task, showed drastically reduced synchrony, measured both by phase-locking of prefrontal cells to hippocampal theta oscillations and by coherence of prefrontal and hippocampal local field potentials. Furthermore, the magnitude of hippocampal–prefrontal coherence at the onset of training could be used to predict the time it took the Df(16)A+/– mice to learn the task and increased more slowly during task acquisition. These data suggest how the deficits in functional connectivity observed in patients with schizophrenia may be realized at the single-neuron level. Our findings further suggest that impaired long-range synchrony of neural activity is one consequence of the 22q11.2 deletion and may be a fundamental component of the pathophysiology underlying schizophrenia.

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Figure 1: Hippocampal–prefrontal synchrony during a spatial working memory task in mice.
Figure 2: Reduced hippocampal–prefrontal synchrony in Df(16)A +/– mice.
Figure 3: Reduced hippocampal–prefrontal synchrony correlates with behavioural performance in Df(16)A +/– mice.
Figure 4: Selectivity of hippocampal–prefrontal synchrony deficits in Df(16)A +/– mice.

References

  1. Stephan, K. E., Friston, K. J. & Frith, C. D. Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring. Schizophr. Bull. 35, 509–527 (2009)

    Article  Google Scholar 

  2. Wernicke, C. Grundrisse der Psychiatrie (Thieme, 1906)

    Google Scholar 

  3. Meyer-Lindenberg, A. S. et al. Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch. Gen. Psychiatry 62, 379–386 (2005)

    Article  Google Scholar 

  4. Lawrie, S. M. et al. Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol. Psychiatry 51, 1008–1011 (2002)

    Article  Google Scholar 

  5. Gottesman, I. I. & Shields, J. A polygenic theory of schizophrenia. Proc. Natl Acad. Sci. USA 58, 199–205 (1967)

    Article  CAS  ADS  Google Scholar 

  6. Karayiorgou, M. & Gogos, J. A. The molecular genetics of the 22q11-associated schizophrenia. Brain Res. Mol. Brain Res. 132, 95–104 (2004)

    Article  CAS  Google Scholar 

  7. Jones, M. W. & Wilson, M. A. Theta rhythms coordinate hippocampal-prefrontal interactions in a spatial memory task. PLoS Biol. 3, e402 (2005)

    Article  Google Scholar 

  8. Ford, J. M., Mathalon, D. H., Whitfield, S., Faustman, W. O. & Roth, W. T. Reduced communication between frontal and temporal lobes during talking in schizophrenia. Biol. Psychiatry 51, 485–492 (2002)

    Article  Google Scholar 

  9. Karayiorgou, M. et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl Acad. Sci. USA 92, 7612–7616 (1995)

    Article  CAS  ADS  Google Scholar 

  10. Xu, B. et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genet. 40, 880–885 (2008)

    Article  CAS  Google Scholar 

  11. The International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008)

  12. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008)

    Article  CAS  ADS  Google Scholar 

  13. Mukai, J. et al. Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion. Nature Neurosci. 11, 1302–1310 (2008)

    Article  CAS  Google Scholar 

  14. Stark, K. L. et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nature Genet. 40, 751–760 (2008)

    Article  CAS  Google Scholar 

  15. Forbes, N. F., Carrick, L. A., McIntosh, A. M. & Lawrie, S. M. Working memory in schizophrenia: a meta-analysis. Psychol. Med. 39, 889–905 (2009)

    Article  CAS  Google Scholar 

  16. Floresco, S. B., Seamans, J. K. & Phillips, A. G. Selective roles for hippocampal, prefrontal cortical, and ventral striatal circuits in radial-arm maze tasks with or without a delay. J. Neurosci. 17, 1880–1890 (1997)

    Article  CAS  Google Scholar 

  17. Siapas, A. G., Lubenov, E. V. & Wilson, M. A. Prefrontal phase locking to hippocampal theta oscillations. Neuron 46, 141–151 (2005)

    Article  CAS  Google Scholar 

  18. Buzsáki, G. et al. Hippocampal network patterns of activity in the mouse. Neuroscience 116, 201–211 (2003)

    Article  Google Scholar 

  19. Kates, W. R. et al. The neural correlates of non-spatial working memory in velocardiofacial syndrome (22q11.2 deletion syndrome). Neuropsychologia 45, 2863–2873 (2007)

    Article  Google Scholar 

  20. Sobin, C. et al. Neuropsychological characteristics of children with the 22q11 deletion syndrome: a descriptive analysis. Child Neuropsychol. 11, 39–53 (2005)

    Article  Google Scholar 

  21. Lewandowski, K. E., Shashi, V., Berry, P. M. & Kwapil, T. R. Schizophrenic-like neurocognitive deficits in children and adolescents with 22q11 deletion syndrome. Am. J. Med. Genet. B 144B, 27–36 (2007)

    Article  Google Scholar 

  22. Bertolino, A. et al. Prefrontal-hippocampal coupling during memory processing is modulated by COMT Val158Met genotype. Biol. Psychiatry 60, 1250–1258 (2006)

    Article  CAS  Google Scholar 

  23. Esslinger, C. et al. Neural mechanisms of a genome-wide supported psychosis variant. Science 324, 605 (2009)

    Article  CAS  ADS  Google Scholar 

  24. Liu, H. et al. Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proc. Natl Acad. Sci. USA 99, 16859–16864 (2002)

    Article  CAS  ADS  Google Scholar 

  25. Mukai, J. et al. Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia. Nature Genet. 36, 725–731 (2004)

    Article  CAS  Google Scholar 

  26. Paterlini, M. et al. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nature Neurosci. 8, 1586–1594 (2005)

    Article  CAS  Google Scholar 

  27. Raux, G. et al. Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome. Hum. Mol. Genet. 16, 83–91 (2007)

    Article  CAS  Google Scholar 

  28. Yavich, L., Forsberg, M. M., Karayiorgou, M., Gogos, J. A. & Mannisto, P. T. Site-specific role of catechol-O-methyltransferase in dopamine overflow within prefrontal cortex and dorsal striatum. J. Neurosci. 27, 10196–10209 (2007)

    Article  CAS  Google Scholar 

  29. Schmitzer-Torbert, N., Jackson, J., Henze, D., Harris, K. & Redish, A. D. Quantitative measures of cluster quality for use in extracellular recordings. Neuroscience 131, 1–11 (2005)

    Article  CAS  Google Scholar 

  30. Kelly, R. C. et al. Comparison of recordings from microelectrode arrays and single electrodes in the visual cortex. J. Neurosci. 27, 261–264 (2007)

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank M. Topiwala, A. Adhikari and Y. Sun for technical assistance. We also thank A. Adhikari, L. Drew and A. Arguello for comments on the manuscript. This work was supported by the Simons Foundation (J. A. Gogos), US National Institute of Mental Health grants MH67068 (M.K. and J. A. Gogos) and MH081968 (J. A. Gordon), and the Lieber Center for Schizophrenia Research and Treatment.

Author Contributions T.S., M.K., J. A. Gogos and J. A. Gordon designed the experiments. T.S. carried out the behavioural and electrophysiology experiments. K.L.S. engineered and supplied the mutant and control mice and contributed to the experimental design. T.S. and J. A. Gordon analysed the data. T.S., M.K., J. A. Gogos and J. A. Gordon interpreted the results and wrote the paper.

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Correspondence to Joseph A. Gogos or Joshua A. Gordon.

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Sigurdsson, T., Stark, K., Karayiorgou, M. et al. Impaired hippocampal–prefrontal synchrony in a genetic mouse model of schizophrenia. Nature 464, 763–767 (2010). https://doi.org/10.1038/nature08855

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