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.
Highlights
The postsynaptic density (PSD) is a highly organized structure attached to the postsynaptic neuronal terminal
As synaptic plasticity is highly dependent on mitochondrial function,[23] energy metabolism acting at the level of the PSD may underpin PSD dysfunction in bipolar disorder and other neuropsychiatric disorders
Identification of PSD proteins and pathways dysregulated in schizophrenia Thirty-six subjects pooled into 18 samples (8 pairs bipolar disorder and 10 pairs of control) were studied (Table 1)
Summary
The postsynaptic density (PSD) is a highly organized structure attached to the postsynaptic neuronal terminal. The reliable quantitation of low-abundance proteins within specific cellular compartments until recently has been challenging and this has led to a shift in the use of prefractionation enrichment methods combined with mass spectrometry-based proteomic techniques. This approach has successfully yielded a detailed characterization of the PSD proteome in rodents and in healthy postmortem human brain tissue.[24] The differential expression of the PSD in schizophrenia compared with controls was first reported recently by our team[25] highlighting altered pathways of endocytosis, long-term potentiation and calcium signaling in schizophrenia. Received 1 April 2016; revised 26 September 2016; accepted 28 September 2016 studies implicating mitochondrial function in major psychiatric disorders)
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