Similar changes in the synaptic proteome of humans with schizophrenia or bipolar disorder and mouse model

Jun 5, 2023 | Diseases & Drugs

The US authors presented results of a large-scale, deep, and unbiased proteomics profiling of synaptic fractions from the postmortem dorsolateral prefrontal cortex of individuals with schizophrenia or bipolar disorder. The study also examined the synaptic proteome of A-kinase anchoring protein 11 (Akap11) mutant mice, a genetic model for both disorders. The findings revealed substantial and similar changes in proteins and molecular pathways in the synaptic proteome of humans with schizophrenia (SCZ) or bipolar disorder (BP). The same pathway changes were observed in synapses purified from Akap11 mutant mice.

SCZ and BP are debilitating psychiatric disorders with lifetime prevalence of approximately 0.4%–0.8% and 1%–2%. Although SCZ and BP are classified as distinct disorders, and have clear differences in typical presentations, they share some clinical and neuropathological features. Human genetic and clinical evidence indicates a significant overlap in the etiology and pathophysiology of SCZ and BP.

Synapse dysfunction has long been considered to be a mechanism underlying SCZ and BP pathophysiology. Researchers observed a decrease in numerous canonical synaptic proteins at SCZ and BP synapses, including glutamate receptors, glutamatergic signaling pathway molecules, and post-synaptic scaffolding proteins. 

About the study

To examine how the protein composition of synapses is altered in SCZ and BP, the researchers purified synaptic fractions from postmortem dorsolateral prefrontal cortex of 35 individuals with SCZ, 35 with BP, and 35 matched controls. The dorsolateral prefrontal cortex (Brodmann’s area 46) is considered to be a brain region of critical importance for both mental disorders.

Mass spectrometry-based quantitative proteomics of each individual sample was carried out. The authors also examined the synaptic proteome of mutant mice deficient in Akap11. Recent exome sequencing in BP has identified AKAP11 as a large-effect risk gene shared with SCZ.

It was found that there were no significant differences in average total protein yields of the purified synaptic fractions between groups, suggesting that there were no gross changes in synapse density between brain samples from SCZ, BP and controls.

But, human SCZ and BP synapses showed highly similar changes in a number of proteins and molecular pathways, including pathways related to synaptic function, vesicle transport, mitochondrial respiration, and mRNA translation. Some of the shared pathway changes in SCZ and BP synapses—notably ribosomal, mitochondrial respiration, and certain vesicle trafficking pathways—were also altered in the same direction in the synaptic proteome of mutant mice deficient in Akap11.

The results also showed that autophagy processes, including mitophagy, ribophagy, and aggrephagy, may be elevated in SCZ and BP synapses. Autophagy is often induced under a variety of stress conditions, such as nutrient/energy stress and redox stress. It is possible that the upregulated autophagy processes reflect cellular stress and contribute to changes in synapse composition in SCZ and BP.

The authors said that decreased content of mitochondria and ribosomal proteins in synapses of patients with SCZ/BP and Akap11-deficient mice could be explained by increased mitophagy and ribophagy. Synaptic mitochondria provide the energy for local translation during synaptic plasticity, among other biological processes. The decreased content of synaptic mitochondria and ribosomal proteins suggests that synaptic protein biosynthesis and synaptic plasticity, processes that have been linked to pathophysiology of neuropsychiatric diseases, may be impaired in SCZ and BP, as well as in Akap11-deficient mice.

In conclusion, this study revealed pronounced molecular changes in synapses purified from postmortem dorsolateral prefrontal cortex of humans with SCZ and BP, and in the cerebral cortex of Akap11-deficient mice, respectively. The important and surprising finding is that synapse proteomes from SCZ and BP showed similar differences compared to control subjects. These findings suggest that common molecular pathomechanisms act at the synapse of these two psychiatric disorders. 

This article was published in Cell Reports.

Journal Reference

Aryal et al., Deep proteomics identifies shared molecular pathway alterations in synapses of patients with schizophrenia and bipolar disorder and mouse model. Cell Reports 42, 112497. May 30, 2023. (Open Access)