title: History of the Concept of Disconnectivity in Schizophrenia.
abstract: 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.
authors.affiliation: From Harvard Medical School and McLean Hospital, Belmont, MA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Coyle
authors.forename: Darrick T
authors.initials: DT
authors.lastname: Balu
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Puhl
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Konopaske
mesh_terms: D001284:Atrophy; D002540:Cerebral Cortex / Q000473:pathology*; D003072:Cognition Disorders / Q000503:physiopathology*; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D015201:Meta-Analysis as Topic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009473:Neuronal Plasticity; D009474:Neurons / Q000473:pathology; D019998:Racemases and Epimerases / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D000099300:Serine Racemase
chemical_list: D009419:Nerve Tissue Proteins; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D000099300:Serine Racemase; C485668:GRIN1 protein, human