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Colorado Team Developing Proteomic Profiles Linked to Learning and Memory

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A team at the University of Colorado, Denver has identified protein profiles associated with learning in mouse models.

Detailed in a paper published this week in Molecular & Cellular Proteomics, the effort is among the first to use proteomics to investigate the molecular underpinnings of learning, Katheleen Gardiner, a UC Denver researcher and senior author on the paper, told ProteoMonitor.

Using reverse phase protein arrays, the researchers measured expression and phosphorylation in more than 80 proteins from the hippocampus and cortex fractions of mice trained in context fear conditioning (CFC), a test of hippocampal function that is used as a measure of normal learning. The measured proteins were either components or interactors of the long term potentiation (LTP) pathway, a pathway key to learning and memory function.

Their analysis found that after an hour of training, levels of more than half the proteins changed in one or both fractions, including 13 proteins previously reported to be dysregulated in Alzheimer's disease, which affects hippocampus function.

They followed this analysis with an effort measuring the same proteins in the brains of mice treated with the Alzheimer's drug memantine, finding that memantine alone induced protein expression and phosphorylation changes similar to those triggered by CFC, including changes to seven of the 13 Alzheimer's-linked proteins. They also found that normal learning was successful both in mice treated and untreated with memantine.

These findings, the authors noted, demonstrate that normal learning leads to considerable modulation of the LTP pathway and that memantine likewise alters the LTP pathway, but in such a manner as to not perturb normal learning.

Research into the molecular processes behind learning have focused primarily on the contributions of a small number of genes, Gardiner said – analyses looking at, for instance, the effect of a mutation in a specific gene on learning in mouse models.

Proteomic-based work like the MCP study, on the other hand, has been rare to non-existent, she said.

Proteomic data are "very complicated" and perhaps "less satisfying because [such analyses] are less sort of mechanistic," she noted. However, she said, "I think it gives you a better reflection of what is happening in the brain if you look at more proteins."

"The [proteomic] experiments that we do can be criticized for not being focused," Gardiner said. "But I happen to think that is an advantage."

She said that while the majority of the proteins the study identified have not been previously studied in the context of learning and memory, of the proteins that have been, their proteomic results "were satisfyingly consistent with prior data."

In addition to the data published in the MCP study, the researchers investigated protein expression in mouse models of Down syndrome with and without treatment with memantine, which rescues learning in Down syndrome mice.

This portion of the work was set aside for another paper due to the large amount of data involved, Gardiner said, but, she noted, the analysis could help shed light on a phenomena currently intriguing Down syndrome researchers – the fact that learning in mouse models can be rescued by a variety of seemingly unrelated drugs.

"There are about 15 drugs or small molecules that have been shown to rescue learning and memory in Down syndrome mouse models, and there is essentially nothing in common as to the targets of these drugs or their mechanisms of action," Gardiner said, noting that agents including Prozac, antioxidants, anti-inflammatories, antagonists of inhibitory neural transmission, antagonists of excitatory neurotransmission, melatonin, and lithium have all been shown to rescue learning in these mice.

Given this, "one of our questions is: What are the common abnormalities that are fixed by these drugs?" she said. "If they all result in normal learning and memory, presumably there is a molecular signature of that success, and if we understood what that signature was, we might identify better [Down syndrome] drugs and better targets."

To that end, the UC, Denver researchers are performing proteomic analyses of the effect of different drugs in a Down syndrome mouse model. To date they have looked at two drugs, and, Gardiner said, they intend to expand the effort to include additional agents. The investigators aren't far enough along yet in analysis of their data, however, to determine if there are any potential protein signatures linking the action of the different drugs.

The researchers are also looking at the effect of a single drug in various mouse models of Down syndrome, Gardiner said, noting that because the genes on human chromosome 21 – an extra copy of which causes the disorder – are spread across three different chromosomes in mice, researchers can't simply "make a single extra chromosome in mice" and have a comprehensive model.

"So we are also looking at these different mouse models that are trisomic for different sets of genes and asking how different and how similar are their protein profiles," she said.

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