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Memory Recall
In day-to-day life, recall of associative memory almost always occurs under the constraints of limited cues. For instance, recalling the rich content of interesting conversations with someone can be triggered by the mere subsequent sighting of that person. In the past, a study of the mechanism underlying this fundamental feature of memory recall, referred to as "pattern completion," has been limited to computational modeling. These theoretical studies hypothesized that a recurrent network with modifiable synaptic strength such as that in hippocampal area CA3 could provide this pattern completion capability. We addressed this issue with the CA3-NR1 KO mice. The evoked NMDA currents and LTP were entirely missing specifically at commissural/association (C/A)-CA3 synapses. The mutant mice were normal in the acquisition and retrieval of spatial memory tested in the standard hidden platform version of the Morris water maze. However, when the memory of the location of the hidden platform was tested following removal of three of the four major extramaze cues (partial cue conditions), the mutants exhibited a clear deficit of memory retrieval compared to the control animals.
To investigate the neural mechanisms that might underlie the specific recall deficit, we examined the neurophysiological consequences of the CA3-NR1 deletion by analyzing CA1 place cell activity (a collaboration with Matthew Wilson). We found that spatial information within CA1 is relatively preserved, despite the loss of CA3 NRs, providing a physiological correlate of the intact spatial performance of the CA3-NR1 KO mice in the Morris water maze under full-cue conditions. To investigate the effect of partial-cue removal on CA1 output, we allowed mice to explore a familiar arena for 20 to 30 minutes under full-cue conditions and then removed them to their home cage. Following a 2-hour delay, mice were returned to the arena with either the same four major extramaze cues present (full-cue conditions) or with three of the four cues removed (partial-cue conditions). In the control mice, there were no significant changes in place field properties associated with the change in the cue conditions, while mutant CA1 cells showed significant reduction in spatial tuning properties. These physiological impairments may underlie the inability of mutants to recall the location of the hidden platform when only partial distal cues are available.
This study, along with our previous study with CA1-NR1 KO mice, illustrates the power of cell-type-restricted, adult-onset gene manipulations in the study of molecular, cellular, and neuronal circuitry mechanisms underlying cognition. This degree of spatial targeting—not to mention the cell-type specificity—is difficult to accomplish by pharmacological manipulation.
This work received support from the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the National Institute on Aging, and RIKEN Institute of Physical and Chemical Research, Japan.
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The Picower Center for Learning and Memory at MIT