Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia

Jennifer L. Zick, Rachael K. Blackman, David A. Crowe, Bagrat Amirikian, Adele L. DeNicola, Theoden I. Netoff, Matthew V. Chafee

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

We employed multi-electrode array recording to evaluate the influence of NMDA receptors (NMDAR) on spike-timing dynamics in prefrontal networks of monkeys as they performed a cognitive control task measuring specific deficits in schizophrenia. Systemic, periodic administration of an NMDAR antagonist (phencyclidine) reduced the prevalence and strength of synchronous (0-lag) spike correlation in simultaneously recorded neuron pairs. We employed transfer entropy analysis to measure effective connectivity between prefrontal neurons at lags consistent with monosynaptic interactions and found that effective connectivity was persistently reduced following exposure to the NMDAR antagonist. These results suggest that a disruption of spike timing and effective connectivity might be interrelated factors in pathogenesis, supporting an activity-dependent disconnection theory of schizophrenia. In this theory, disruption of NMDAR synaptic function leads to dysregulated timing of action potentials in prefrontal networks, accelerating synaptic disconnection through a spike-timing-dependent mechanism. Zick et al. report that blocking NMDAR reduces 0-lag spike correlation and persistently reduces functional coupling between neurons in monkey prefrontal local circuits. NMDAR synaptic dysfunction in schizophrenia could similarly disrupt spike timing and disconnect prefrontal circuits via an activity-dependent process.

Original languageEnglish (US)
Pages (from-to)1243-1255.e5
JournalNeuron
Volume98
Issue number6
DOIs
StatePublished - Jun 27 2018

Bibliographical note

Funding Information:
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 ( R01MH077779 and R01MH107491 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 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.), MnDrive Neuromodulation Fellowship (to A.L.D.), American Brain Sciences Chair , and the Department of Veterans Affairs (to B.A.). 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 U.S. Department of Veterans Affairs or the United States Government.

Keywords

  • NMDAR antagonist
  • STDP
  • animal model
  • cross correlation
  • effective connectivity
  • neural synchrony
  • nonhuman primate
  • spike correlation
  • transfer entropy

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