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History of the Concept of Disconnectivity in Schizophrenia

Coyle, Joseph T. MD; Balu, Darrick T. PhD; Puhl, Matthew D. PhD; Konopaske, Glenn T. MD

doi: 10.1097/HRP.0000000000000102

Nearly 60 years ago Seymour Kety proposed that research on genetics and brain pathology, but not on neurochemistry, would ultimately lead to an understanding of the pathophysiology of schizophrenia. This article will demonstrate the prescience of Kety’s proposal; advances in our knowledge of brain structure and genetics have shaped our current understanding of the pathophysiology of schizophrenia. Brain-imaging techniques have shown that schizophrenia is associated with cortical atrophy and ventricular enlargement, which progresses for at least a decade after the onset of psychotic symptoms. Cortical atrophy correlates with negative symptoms and cognitive impairment, but not with psychotic symptoms, in schizophrenia. Studies with the Golgi-staining technique that illuminates the entire neuron indicate that cortical atrophy is due to reduced synaptic connectivity on the pyramidal neurons and not due to actual loss of neurons. Results of recent genetic studies indicate that several risk genes for schizophrenia are within two degrees of separation from the N-methy-D-aspartate receptor (NMDAR), a subtype of glutamate receptor that is critical to synapse formation and synaptic plasticity. Inactivation of one of these risk genes that encodes serine racemase, which synthesizes D-serine, an NMDAR co-agonist, reproduces the synaptic pathology of schizophrenia. Thus, widespread loss of cortical synaptic connectivity appears to be the primary pathology in schizophrenia that is driven by multiple risk genes that adversely affect synaptogenesis and synapse maintenance, as hypothesized by Kety.

From Harvard Medical School and McLean Hospital, Belmont, MA.

Original manuscript received 24 April 2015, accepted for publication subject to revision 25 June 2015; revised manuscript received 17 July 2015.

Supported by National Institutes of Health grant nos. R01MH05190 and P50MH0G0450 (Dr. Coyle) and K99MH099252-01 (Dr. Balu).

Correspondence: Joseph T. Coyle, MD, McLean Hospital, 115 Mill St., Belmont, MA 02478. Email:

© 2016 President and Fellows of Harvard College
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