Fwd: Memories are made of these

From: Wade T.Smith (wade_smith@harvard.edu)
Date: Fri Mar 08 2002 - 14:00:52 GMT

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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
    simply overloads.

    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.

    This was distributed via the memetics list associated with the
    Journal of Memetics - Evolutionary Models of Information Transmission
    For information about the journal and the list (e.g. unsubscribing)
    see: http://www.cpm.mmu.ac.uk/jom-emit

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