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USC Researchers Identify Brain Signaling Changes Linked to Autism, Schizophrenia


NEW YORK (GenomeWeb) – A team led by researchers at the University of Southern California has identified brain signaling and protein interaction changes that appear to be linked to various psychiatric disorders.

In a study published this week in Science Signaling, the researchers looked at changes in the phosphoproteome and interactome of the postsynaptic density (PSD) in response to hippocampal long-term potentiation (LTP), finding that LTP triggered significant changes in PSD signaling, including changes to a number of proteins linked to autism and schizophrenia.

Long-term potentiation is a form of synaptic plasticity in which synaptic connections are strengthened, enhancing transmission across them. It leads to a variety of cellular changes including alterations in gene and protein expression and neuron morphology and is thought to be linked to processes involved in learning and memory.

For many years, neurologists debated whether LTP was primarily a pre-synaptic or post-synaptic phenomenon, said Marcelo Coba, a USC researcher and senior author on the paper. Today, he noted, the community has reached a consensus that it is largely post-synaptic.

"And at the post-synaptic site (or PSD), you have a collection of around 1,500 proteins," he said. "But not many people have analyzed [on a large scale] the structure of the signaling mechanisms in the PSD."

In particular, Coba and his co-authors noted, relatively little work has been done looking at large-scale PSD protein signaling changes in response to induction of LTP. The LTP phenomenon "has been known for more than 40 years," he said, "but people have been analyzing molecules one by one, basically."

To generate a more comprehensive picture of LTP-induced changes in PSD protein signaling, the researchers used mass spec analysis of a specific portion of the hippocampus — the CA1 region — that has been a focus of LTP research.

Using mice aged eight to 12 weeks, the researchers removed their CA1 regions and cut them into slices, using 20 slices per assay. They then induced LTP using high-frequency, tetanic stimulation, snap-freezing the slices five minutes after this stimulation along with control samples of unstimulated CA1 slices.

The process is a fairly tedious one, Coba noted. "You need to stimulate these slices one by one, collect the proper controls also one by one, and then before we go to the mass spec we do some Western blots to check that some key molecules have been properly accumulated," he said. "It is not easy, and it took us some time to get to the protocol we are using, but it is now pretty stable."

Using this approach, the researchers identified 222 PSD proteins and 570 phosphorylation sites altered by LTP induction. In total, they identified 1,626 PSD proteins including 81 protein kinases and 20 protein phosphatases.

Among the most striking findings to emerge from this analysis, Coba said, was that proteins significantly associated with schizophrenia and autism saw alterations in their phosphorylation patterns in response to LTP.

Mutations in PSD proteins have been linked to a variety of psychiatric disorders, and with this in mind the researchers looked at whether the CA1 PSD sections they were investigating were enriched for disease-linked proteins and whether these proteins' phosphorylation states appeared to be altered by LTP induction.

Their analysis found CA1 PSD was, in fact, enriched for proteins linked to autism and schizophrenia and that these proteins were regulated by LTP. Removing these LTP-regulated proteins from consideration, they no longer found any significant enrichment for these disorders in the PSD proteome, indicating, they wrote, "that the risk for these two psychiatric diseases …  tends to be associated with proteins modulated by the induction of LTP."

Using immunoprecipitation mass spec, the researchers also found that induction of LTP changed the composition of disease-linked protein complexes containing these proteins.

Coba said he and his colleagues are now further investigating particular protein-protein interactions that they identified as disease-linked in a more targeted manner. Additionally, he noted, they hope to model PSD protein signaling under different types of LTP induction and in different phases of induction.