Feature Finding Figure

Altered Glutamate Protein Co-Expression Network Topology Linked to Spine Loss in the Auditory Cortex of Schizophrenia

Impaired glutamatergic signaling is believed to underlie auditory cortex pyramidal neuron dendritic spine loss and auditory symptoms in schizophrenia. Many schizophrenia risk loci converge on the synaptic glutamate signaling network. We therefore hypothesized that alterations in glutamate signaling protein expression and co-expression network features are present in schizophrenia. Gray matter homogenates were prepared from auditory cortex grey matter of 22 schizophrenia and 23 matched controls, a subset of whom had been previously assessed for dendritic spine density. 155 selected synaptic proteins were quantified by targeted mass spectrometry. Protein co-expression networks were constructed using Weighted Gene Co-Expression Network Analysis. Proteins with evidence for altered expression in schizophrenia were significantly enriched for Glutamate Signaling Pathway proteins (GRIA4, GRIA3, ATP1A3 and GNAQ). Synaptic protein co-expression was significantly decreased in schizophrenia with the exception of a small group of postsynaptic density proteins, whose co-expression increased and inversely correlated with spine density in schizophrenia subjects (Figure). We observed alterations in the expression of Glutamate Signaling Pathway proteins. Among these, the novel observation of reduced ATP1A3 expression is supported by strong genetic evidence indicating it may contribute to psychosis and cognitive impairment phenotypes. The observations of altered protein network topology further highlights the complexity of glutamate signaling network pathology in schizophrenia and provides a framework for evaluating future experiments to model the contribution of genetic risk to disease pathology.
MacDonald ML, Ding Y, Newman J, Hemby S, Penzes P, Lewis, David, Yates N, Sweet RA: Altered Glutamate Protein Co-Expression Network Topology Linked to Spine Loss in the Auditory Cortex of Schizophrenia. Biol Psychiatry, in press.

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