Princeton, NJ (9/2/99)- Adding a gene that encourages extra production
of a common neurotransmitter appears to boost both the memory and learning
ability of experimental animals. While the finding is not likely to translate
into "smart pills" for sluggish science students anytime soon, it
is likely that insights gained from this discovery may indeed lay the groundwork
for treatments of many neurological disorders.
Researchers at Princeton University created a strain of genetically engineered
mice with an extra gene called NR2B. The gene triggers production of extra
amounts of a receptor for the neurotransmitter NMDA (N-methyl-D-aspartate)
in the forebrains of the animals. NMDA is known to be an essential element
in the neurological processes of learning and memory. The increased activity
of the receptors was associated with "superior ability in learning and memory
in various tasks" in the mice compared to that seen among control animals.
The researchers dubbed the new strain of mouse "doogie" after the
TV character Doogie Howser, a precocious student who entered medical school
in his teen years.
LEFT:
A "Doogie"
mouse stands on an object used in a learning and memory test. In the novel
object recognition test, the mice were given the chance to become familiar
with two objects. Later, when one object was switched for another, Doogie
mice quickly recognized the switch and devoted time to exploring the new object
instead of the old one. Normal mice spent equal time exploring the new object
and the old one.
The research provides new support for a neurological mechanism of learning
and memory first proposed 50 years ago by the pioneering researcher Donald
O. Hebb. He had proposed that learning and memory depended on modifications
of synaptic strength among neurons that were simultaneously active. The new
research confirms that the NMDA receptor works as a kind of coincidence detector.
As signal detection by NMDA receptors increases, learning and memory processes
are enhanced. Moreover, this relatively simple pathway appears to be the basis
for virtually all learning and memory.
The NR2B gene encodes the protein that forms the NMDA receptor. The NMDA
receptor needs two signals from the neurotransmitter before it becomes active.
For example, it may receive near simultaneous information linking a lit match
and a sensation of pain and build a memory based on that coincidence.
RIGHT
Double-Keyed
Lock. Neurons are equipped with a "coincidence detector" called the NMDA receptor
that is triggered only when it receives two signals from independent sources.
When it senses such a coincidence, it responds by opening a gate in the cell
membrane. In the first picture above, the NMDA receptor is blocked by a magnesium
ion. In the second picture, the two signals occur simultaneously: 1) neuron
A emits a signal in the form of a glutamate molecule, which binds to the NMDA
receptor on neuron B; and 2) the cell membrane of neuron B undergoes a reversal
of electrical charge, called depolarization. When both these steps occur,
in the final picture, the magnesium ion gets kicked out of the NMDA gate,
the channel opens and calcium ions start flowing into the cell. This initiates
a chain of events that leads to learning.
The 'doogie' mouse research also may help explain why learning ability is
at its peak during youth and diminishes with age, a phenomenon observed across
the animal kingdom. Previous studies have shown that the NMDA receptor becomes
less responsive after adolescence. The Princeton researchers not only inserted
extra NR2B genes into the 'doogie' mice, they engineered them in such a way
that the receptors would become more, rather than less, active with age.The
experimental mice did better on intelligence tests both in the juvenile and
adult stages of life.
The research also provides support for the idea that memories are created
when two neurons form a strong connection, called long-term potentiation or
LTP. This study offers "one of the best pieces of evidence so far" in favor
of the LTP model, because activating the NMDA receptor clearly leads to LTP,
notes Charles Stevens, a neuroscientist at the Salk Institute and an expert
in the biological underpinnings of memory.
In the short term, the new findings will open new avenues in the study of
learning and memory. Over the longer term, these findings are likely to form
the basis for new drugs and genetic therapies for the treatment of many human
neurological disorders such as Alzheimer's disease, schizophrenia and dementia.
The research appeared in the September 2, 1999 issue of the journal Nature,
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