Picking Apart How Neurons Learn

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Picking Apart How Neurons Learn

http://www.medicalnewstoday.com/medicalnews.php?newsid=40641

s 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 March issue of 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 L. Huganir, Ph.D., a

Medical Institute investigator and chair of the

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.

The researchers were funded by the National Institutes of Health, the

Packard Center for ALS Research, the Muscular Dystrophy

Association's Wings Over Wall Street, Public Health Service, the

Develbiss Fund, and Research Grants Council of Hong Kong