Targeted mutations in mice uncover two key molecular events linked to learning

Johns Hopkins researchers have used mouse mutants to define critical steps involved in learning basic motor skills. The study focuses on the behavior of two proteins and the specific steps they take to control a neuron's ability to learn by adapting to signals from other nerve cells.

The findings, published in the journal Neuron, pull together a growing body of evidence from the field. The study shows definitively that interactions between the PICK1 protein and another group of proteins known as AMPA receptors are critical for specific neurons, called Purkinje cells, in the lower back part of the brain to become de-sensitized to certain molecular signals.

Desensitization to molecular signals from neighboring neurons - a process known as long-term depression, or LTD - is thought to be responsible for several forms of motor learning, one of which is known as the vestibulo-ocular reflex. The vestibulo-ocular reflex coordinates eye movements with head movements, allowing us to perform activities such as reading in a moving automobile.

"We've long known that LTD underlies responses like the vestibulo-ocular reflex. This study gets at the heart of how LTD occurs, specifically how PICK1 controls the Purkinje cell's response to the signaling molecule, glutamate," says Richard L. Huganir, Ph.D., a Howard Hughes Medical Institute investigator and chair of the Solomon H. Snyder Department of Neuroscience at Hopkins.

The first critical step in establishing LTD happens when Purkinje cells swallow up surface proteins called AMPA receptors. Without AMPA receptors on the surface, these cells no longer are able to respond to signals from neighboring neurons. Researchers had known that PICK1 somehow was involved in the swallowing and removal of AMPA receptors, but only in this most recent study did they reveal how.

The investigators used individual nerve cells as well as brain slices from three different populations of genetically modified mice lacking different proteins required for establishing LTD.

Mice lacking the PICK1 protein are unable to establish LTD or remove AMPA receptors from cell surfaces. When PICK1 is added artificially back into these neurons, AMPA receptors are removed and LTD is restored, showing that PICK1 is necessary for LTD.

Mice lacking the part of the AMPA receptor thought to physically interact with PICK1 also do not establish LTD. This result confirms that PICK1 must physically touch the AMPA receptor for LTD to occur.

The second critical step in establishing LTD involves a chemical change to the AMPA receptor, called phosphorylation. Mice lacking a small part of the AMPA receptor - the part where phosphorylation is thought to occur - do not undergo LTD. This result confirms that phosphorylation is an essential step toward LTD.

With these three different mouse populations in hand, the research team is poised to further dissect the molecular mechanisms behind learning. "The next step is to determine whether LTD is crucial for motor learning, the so-called holy grail in the field," says one of the study's co-first authors, Jordan Steinberg, an M.D., Ph.D. candidate at Hopkins.

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