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Schizophrenia as a Disorder of Developmentally Reduced Synaptic Connectivity

Thomas H. McGlashan, md; Ralph E. Hoffman, md
Arch Gen Psychiatry. 2000;57(7):637-648. doi:10-1001/pubs.Arch Gen Psychiatry-ISSN-0003-990x-57-7-ynv9397.
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Recent postmortem and neuroimaging studies of schizophrenia delineate changes in brain structure and volume that appear to arise from a reduction of neuritic processes (such as dendrites and synapses) rather than loss of neuronal or glial cell bodies. To account for these findings, we propose a pathophysiological model of reduced synaptic connectivity arising from disturbances of brain development active during perinatal and adolescent periods. We review a computer simulation of the elimination of the synaptic connections that models normal cognitive development and psychotic symptom formation. We describe the model's key parameters and discuss how they can account for important aspects of schizophrenia, including its unique symptoms, short- and long-term course, typical age of onset, neurodevelopmental deficits, limited neurodegenerative progression, sex differences, and more. We discuss some of the model's predictions and questions raised for basic research, early detection, and preventive intervention.

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Figure 1.

Data generated from computer model described by Hoffman and McGlashan.60 Network performance from 5 different trials using different sets of random numbers to phonetically degrade inputs were averaged together. Connections are pruned according to a "darwinian rule"; ie, weaker connections (both excitatory and inhibitory) are eliminated. Net reduction in synapses was estimated by assuming that connection strength between 2 neurons generated by the computer model has a linear correlation with the number of "synapses" required to sustain that connection. The top tracing corresponds to words correctly generated (identified) from degraded inputs. The lower tracing shows emergence of perceptual outputs in the absence of inputs corresponding to "hallucinations."

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Figure 2.

Model of reduced synaptic density over time and the development of schizophrenia with constant pruning rate but variable level of synaptic density at baseline. I indicates normal; II, mild schizophrenia; III, moderate schizophrenia; and IV, severe schizophrenia. A, D, and G indicate prodromal onset points; B, E, H, psychosis onset points; and C, F, H, and I, plateau or point of maximal degeneration from pruning.

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Figure 3.

Model of reduced synaptic density over time and the development of schizophrenia with constant baseline synaptic density but variable pruning rate. I indicates normal; II, mild schizophrenia; III, moderate schizophrenia; and IV, severe schizophrenia. A, D, and G indicate prodromal onset points; B, E, H, psychosis onset points; and C, F, H, and I, plateau or point of maximal degeneration from pruning.

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