Disparate insults relevant to schizophrenia converge on impaired spike synchrony and weaker synaptic interactions in prefrontal local circuits

Jennifer Zick, David A Crowe, Rachael K Blackman, Kelsey Schultz, David W. Bergstrand, Adele L DeNicola, Russell E Carter, Timothy J. Ebner, Lorene M. Lanier, Theoden I. Netoff, Matthew V. Chafee

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Schizophrenia results from hundreds of known causes, including genetic, environmental, and developmental insults that cooperatively increase risk of developing the disease. In spite of the diversity of causal factors, schizophrenia presents with a core set of symptoms and brain abnormalities (both structural and functional) that particularly impact the prefrontal cortex. This suggests that many different causal factors leading to schizophrenia may cause prefrontal neurons and circuits to fail in fundamentally similar ways. The nature of convergent malfunctions in prefrontal circuits at the cell and synaptic levels leading to schizophrenia are not known. Here, we apply convergence-guided search to identify core pathological changes in the functional properties of prefrontal circuits that lie downstream of mechanistically distinct insults relevant to the disease. We compare the impacts of blocking NMDA receptors in monkeys and deleting a schizophrenia risk gene in mice on activity timing and effective communication in prefrontal local circuits. Although these manipulations operate through distinct molecular pathways and biological mechanisms, we found they produced convergent pathophysiological effects on prefrontal local circuits. Both manipulations reduced the frequency of synchronous (0-lag) spiking between prefrontal neurons and weakened functional interactions between prefrontal neurons at monosynaptic lags as measured by information transfer between the neurons. The two observations may be related, as reduction in synchronous spiking between prefrontal neurons would be expected to weaken synaptic connections between them via spike-timing-dependent synaptic plasticity. These data suggest that the link between spike timing and synaptic connectivity could comprise the functional vulnerability that multiple risk factors exploit to produce disease.

Original languageEnglish (US)
Pages (from-to)14-25.e4
JournalCurrent Biology
Volume32
Issue number1
DOIs
StatePublished - Jan 10 2022

Bibliographical note

Funding Information:
We thank David Redish and Sophia Vinogradov for providing useful editorial comments on the manuscript. We thank Bagrat Amirikian for refinements of the CCH 0-lag and TE analysis. We thank Dean Evans for lab and project management as well as his assistance with surgeries, animal care, and neural recordings; Dale Boeff for his assistance with neurophysiological recording system design and construction, as well as computer programming for signal processing and data analysis; Sofia Sakellaridi for her assistance with neural recordings; and Aisha Mohamed for her assistance with preliminary data analysis. Support for this work was provided by the National Institute of Mental Health (R01MH107491 and P50MH119569 to M.V.C. 5F30MH108205-02 to J.L.Z. R25 MH101076 to R.K.B. and F31MH109238 to A.L.D.), the National Institute of General Medical Sciences (T32 GM008244 and T32 HD007151 to R.K.B. and T32GM847121 to A.L.D.), Wilfred Wetzel Graduate Fellowship (to R.K.B.), Minnesota Medical Foundation (to M.V.C. and T.I.N.), Winston and Maxine Wallin Neuroscience Discovery Fund (to M.V.C. L.M.L. and T.I.N.), and MnDrive Neuromodulation Fellowship (to A.L.D.). This material is the result of work supported with resources and the use of facilities at the Minneapolis VA Health Care System. The contents do not represent the views of the US Department of Veterans Affairs, the National Institutes of Health, the Department of Health and Human Services, or the United States government. This manuscript was prepared while R.K.B. was employed at the University of Minnesota. The opinions expressed in this article are the author's own and do not reflect the views of the National Institutes of Health, the Department of Health and Human Services, or the United States government. Conceptualization, J.L.Z. T.I.N. and M.V.C.; methodology, J.L.Z. R.K.B. K.S. A.L.D. R.E.C. L.M.L. and M.V.C.; software, J.L.Z. D.A.C. R.K.B. D.W.B. and M.V.C.; validation, J.L.Z. and D.A.C.; formal analysis, J.L.Z. D.A.C. and T.I.N.; investigation, J.L.Z. R.K.B. K.S. A.L.D. and R.E.C.; writing ? original draft, J.L.Z. and M.V.C. (primary); writing ? review & editing, J.L.Z. D.A.C. R.K.B. K.S. A.L.D. T.J.E. L.M.L. T.I.N. and M.V.C.; visualization, J.L.Z. D.A.C. and M.V.C.; supervision, T.J.E. T.I.N. and M.V.C.; resources, L.M.L. T.J.E. and M.V.C.; funding acquisition, T.I.N. and M.V.C. The authors declare no competing interests.

Funding Information:
We thank David Redish and Sophia Vinogradov for providing useful editorial comments on the manuscript. We thank Bagrat Amirikian for refinements of the CCH 0-lag and TE analysis. We thank Dean Evans for lab and project management as well as his assistance with surgeries, animal care, and neural recordings; Dale Boeff for his assistance with neurophysiological recording system design and construction, as well as computer programming for signal processing and data analysis; Sofia Sakellaridi for her assistance with neural recordings; and Aisha Mohamed for her assistance with preliminary data analysis. Support for this work was provided by the National Institute of Mental Health ( R01MH107491 and P50MH119569 to M.V.C., 5F30MH108205-02 to J.L.Z., R25 MH101076 to R.K.B., and F31MH109238 to A.L.D.), the National Institute of General Medical Sciences ( T32 GM008244 and T32 HD007151 to R.K.B. and T32GM847121 to A.L.D.), Wilfred Wetzel Graduate Fellowship (to R.K.B.), Minnesota Medical Foundation (to M.V.C. and T.I.N.), Winston and Maxine Wallin Neuroscience Discovery Fund (to M.V.C., L.M.L., and T.I.N.), and MnDrive Neuromodulation Fellowship (to A.L.D.). This material is the result of work supported with resources and the use of facilities at the Minneapolis VA Health Care System. The contents do not represent the views of the US Department of Veterans Affairs, the National Institutes of Health, the Department of Health and Human Services, or the United States government. This manuscript was prepared while R.K.B. was employed at the University of Minnesota. The opinions expressed in this article are the author’s own and do not reflect the views of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • Dgcr8
  • NMDA
  • monkey
  • mouse
  • prefrontal cortex
  • schizophrenia
  • spike timing

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