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Altered Glutamate Protein Co-Expression Network Topology Linked to Spine Loss in the Auditory Cortex of Schizophrenia
MacDonald ML, Ding Y, Newman J, Hemby S, Penzes P, Lewis, DA, Yates N, and Sweet RA
Biological Psychiatry, in press

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. Dr. Matthew MacDonald and his colleagues in the laboratory of Dr. Robert Sweet 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 comparison subjects, a subset of whom had been previously assessed for dendritic spine density. One hundred and fifty -five 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 subjects with the exception of a small group of postsynaptic density proteins, whose co-expression increased and inversely correlated with spine density. The investigators observed alterations in the expression of Glutamate Signaling Pathway proteins. Among these, the novel observation of reduced ATP1A3 expression was supported by strong genetic evidence that 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.  

Contributors:
Matthew L. MacDonald, MD, PhD, Jason Newman, PhD, David A. Lewis, MD, and Robert A. Sweet, MD (Department of Psychiatry, University of Pittsburgh School of Medicine)

Ying Ding, PhD (Department of Biostatistics, University of Pittsburgh Graduate School of Public Health)

Nathan Yates, PhD (Department of Cell Biology, University of Pittsburgh)

Scott Hemby, PhD (School of Pharmacy, High Point University)

Peter Penzes, PhD (Feinberg School of Medicine, Northwestern University)

This article is currently in press in Biological Psychiatry.  Click here to view the abstract.