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Individuals with schizophrenia often exhibit impairments in the processing of auditory sensory information and auditory learning. Previous research has implicated the involvement of synaptic protein networks in the pathology of schizophrenia. 

The number, type and strength of connections between synapses are governed in large part by complex protein networks. “In order for the synapse to function, many different proteins have to work in concert, functioning as a complex machine,” said Matthew MacDonald, PhD, lead author on a study published in JAMA Psychiatry. “We have reason to believe that a breakdown of this machinery underlies the impairments in synaptic connections that underlie many of the symptoms of schizophrenia.”

Previous studies had examined levels of the messenger RNA—the intermediate messenger between the genome and this complex proteome machinery. When the gene is transcribed to a messenger RNA, this message is then used to create the protein. Many studies have shown that the levels of these messages, for mitochondrial and synaptic proteins, are altered in individuals with schizophrenia. However, for Dr. MacDonald and his colleagues, including Department of Psychiatry faculty members Jill Glausier, PhD, David Lewis, MD, and Robert Sweet, MD, these studies presented an opportunity to examine the levels using a different approach. “We suspected that there could be something wrong with the protein that isn’t reflected in the alterations in the message. We decided to look a few steps down the chain to the levels of these different parts of the machine within the synapse.” The investigators hypothesized that in individuals with schizophrenia, the protein levels at the synapse are altered in the primary auditory cortex, and that these alterations are distinct from protein alterations in total gray matter.

The team looked at the levels of individual proteins within the synapse in human postmortem brain tissues from 48 pairs of schizophrenia and matched control subjects. They found that the levels within the synapse were strongly altered. Additionally, they found that these alterations were not reflected in or explained by alterations in the levels of the protein in the whole cell. “So, the message could be fine, the levels of the proteins across the whole cell could be fine, but the levels of the proteins within the synaptic compartment were not fine,” explains Dr. MacDonald. 

Regarding the implications for further research, senior author Dr. Sweet noted, “This finding provides a road map for identifying the mechanisms driving these synaptic protein alterations was well as the synaptic subtypes that may be specifically impaired.”

Synaptic Proteome Alterations in the Primary Auditory Cortex of Individuals with Schizophrenia
MacDonald ML, Garver M, Newman J, Sun Z, Kannarkat J, Salisbury R, Glausier J, Ding Y, Lewis DA, Yates N, Sweet RA
JAMA Psychiatry. Published online October 23, 2019