Feature Finding Title
Feature Finding Figure

Converging lines of evidence indicate that schizophrenia is characterized by impairments of synaptic machinery within cerebral cortical circuits. Efforts to localize these alterations in brain tissue from subjects with schizophrenia have frequently been limited to the quantification of structures that are non-selectively identified (e.g. dendritic spines labeled in Golgi preparations, axon boutons labeled with synaptophysin), or to quantification of proteins using methods unable to resolve relevant cellular compartments. Multiple label fluorescence confocal microscopy represents a means to circumvent many of these limitations, by concurrently extracting information regarding the number, morphology, and relative protein content of synaptic structures. An important adaptation required for studies of human disease is coupling this approach to stereologic methods for systematic random sampling of relevant brain regions. In this review article we consider the application of multiple label fluorescence confocal microscopy to the mapping of synaptic alterations in subjects with schizophrenia and describe the application of a novel, readily automated, iterative intensity/morphological segmentation algorithm for the extraction of information regarding synaptic structure number, size, and relative protein level from tissue sections obtained using unbiased stereological principles of sampling. In this context, we illustrate the examination of pre- and post-synaptic structures within excitatory and inhibitory circuits of the cerebral cortex. For example, the figure above shows human primary auditory cortex tissue labeled for synaptophysin (Synph, green), vesicular glutamate transporter 2 (VGlut2; blue), and vesicular glutamate transporter (VGlut1; red). In panels A-D, arrows demonstrate colocalization between synaptophysin and either VGlut1 or VGlut2. Panel E shows VGlut2 and synaptophysin fluorescence intensities extracted from mask objects of the VGlut1-immunoreactive boutons in the micrographs shown in panels A-D, demonstrating that quantitative data reflecting the degree of colocalization are readily extracted. Bar = 5 Ám.

Sweet RA, Fish KN and Lewis DA: Mapping synaptic pathology within cerebral cortical circuits in subjects with schizophrenia. Front. Hum. Neurosci 4: 44, 2010.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
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