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Abstract:
We have been studying molecular, cellular, and neuronal
ensemble mechanisms underlying cognitive functions such as learning
and memory by developing and applying conditional transgenic and
gene knockout techniques in mice. Using the Cre/loxP recombination
system, we developed a method to target gene knockout to the CA1
layer of the hippocampus, a neural tissue known to play a crucial
role in the acquisition and consolidation of memory of events and
facts. We applied this technique to the essential subunit of the
NMDA subtype of glutamate receptors. Electrophysiological,
hybridization, and immunohistological data indicate that the
deficiency of NMDA receptors occurs preferentially at the Schaeffer
collateral-CA1 pyramidal cell synapses as long as the ages of the
mutant mice are in a certain range. No NMDA receptor-dependent LTP
or LTD can be induced at these synapses although upotentiated
synaptic transmission mediated by AMPA subtype of glutamate
receptors is apparently normal. These CA1-specific NRI knockout
(CA1-NRIKO) mice fail to acquire hippocampus-dependent memory
including spatial memory and to form normal neuronal ensemble codes
of space (place cells) in the CA1 area. The data provide the
strongest evidence for the Hebbian hypothesis that memory is
encoded in a set of potentiated synapses and demonstrate
hippocampal CA1 synapses play a crucial role in spatial learning
and/or memory. We have also shown that the CA1-NRIKO mice fail in
tasks that require association of two temporally disjoined events.
An example is a fear-based conditioning in which a neutral tone is
given as the conditioned stimulus (CS) 30 seconds prior to an
electric shock to the foot pads as the unconditioned stimulus (US).
In contrast to normal animals CA1-NRIKO mice failed in being
conditioned in this paradigm despite the fact that both types of
animals are conditioned in a slightly altered paradigm where CS and
US are temporally conjugated. Thus, the hippocampus and more
specifically NMDA receptors in the CA1 area is needed in memory
tasks that require an association in both spatial and temporal
domains.
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