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.