Proteomic analysis of the postsynaptic density implicates synaptic function and energy pathways in bipolar disorder.

ABSTRACT

The postsynaptic density (PSD) contains a complex set of proteins of known relevance to neuropsychiatric disorders such as schizophrenia and bipolar disorder. We enriched for this anatomical structure in the anterior cingulate cortex of 16 bipolar disorder samples and 20 controls from the Stanley Medical Research Institute. Unbiased shotgun proteomics incorporating label-free quantitation was used to identify differentially expressed proteins. Quantitative investigation of the PSD identified 2033 proteins, among which 288 were found to be differentially expressed. Validation of expression changes of DNM1, DTNA, NDUFV2, SEPT11 and SSBP was performed by western blotting. Bioinformatics analysis of the differentially expressed proteins implicated metabolic pathways including mitochondrial function, the tricarboxylic acid cycle, oxidative phosphorylation, protein translation and calcium signaling. The data implicate PSD-associated proteins, and specifically mitochondrial function in bipolar disorder. They relate synaptic function in bipolar disorder and the energy pathways that underpin it. Overall, our findings add to a growing literature linking the PSD and mitochondrial function in psychiatric disorders generally, and suggest that mitochondrial function associated with the PSD is particularly important in bipolar disorder.