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Memories are made of these
by Damaris Christensen, BioMedNet News
7 March 2002 16:30 EST
Elegant research released today from Nobelist Eric Kandel's laboratory
reveals that the cAMP response element binding protein (CREB), long
implicated in memory consolidation, primes brain cells to retain
long-term memories. Regulated expression of CREB, during or shortly
before a memory task, might allow single-trial learning, and eventually
lead to development of memory-enhancing drugs, Kandel says.
In general, nerve cells become more tightly linked when stimulated by a
series of high-frequency electrical pulses, says Kandel, professor of
physiology at Columbia University. This increase in synaptic strength -
known as long-term potentiation, or LTP - may last for hours, days or
even weeks, and is critical in learning and memory formation.
Kandel and his colleagues engineered mice to express a chimeric CREB
protein with an acidic transactivation domain from HSV-VP16, sensitive to
the antibiotic doxycycline. Compared to neurons from wild-type mice,
neurons in the engineered mice need a smaller first stimulus to generate
a lasting increase in synaptic strength, Kandel says.
"You need to store information, and information storage may require new
building blocks," said John Lisman, professor of biology at Brandeis
University. "This is one more step in showing that CREB has the power to
provide these building blocks for a local process of synaptic
CREB is thought to activate a number of genes that act in concert to
produce synaptic changes associated with LTP. "Overexpressing CREB primes
all of the synapses so that if you just weakly kiss any of those synapses
you can capture a response to that signal," Kandel explained.
In wild-type mice, a single 100 Hz tetanus train - a series of quickly
repeated electric pulses - lasting for 1 second, produces a
non-saturating, short-lasting LTP. In mice overexpressing CREB, the same
tetanic train evoked an enhanced LTP lasting at least 3 hours. The
results are published today in Cell.
Feeding the VP16-CREB mice with doxycyline, which turns off expression of
the chimeric VP16-CREB, for 2-3 weeks reversed the effects, so the mice
responded normally to tetanic stimulation, Kandel reports.
The transgenic CREB did not affect basal synaptic activity, although it
did upregulate a number of genes activated by CREB, Kandel says. "Our
data indicate that CRE-mediated transcription is one of the prerequisites
for the consolidation of long-term synaptic changes," said Kandel.
Specifically, he adds, VP16-CREB activity can lead to cell-wide priming
for LTP by seeding the synaptic terminals with proteins and mRNAs
required for the stabilization and capture of long-term LTP.
That can be good and bad, Kandel says. Preliminary tests of behavior in
the engineered mice suggest they have trouble remembering navigational
cues. That's because once a nerve cell is primed to respond to one
signal, it can't unlearn the signal through depotentiation, and the brain
Kandel and his team are now testing whether they can using doxycycline to
turn the VP16-CREB on and off so that the mice can be primed to remember
certain tasks very well without chronic boosting of LTP. If so, Kandel
says, it suggests that it may eventually be possible to design drugs to
briefly boost a person's memory.
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