. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron. 2001 Dec 6;32(5):911-26. PubMed.

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  1. "This paper presents a fascinating, two-part hypothesis. It suggests that presenilin-1 is necessary for neurogenesis in the dentate gyrus of mice that have been stimulated by exposure to an enriched environment. It goes on to propose that a biological function of dentate gyrus neurogenesis may be to clear outdated memory traces from the hippocampus so that the hippocampus can remain continually available for newly formed memories once older ones have been consolidated in the cortex.

    Clearly, this idea intrigues those interested in the memory deficits of Alzheimer's, (though note that the PS-1 mutations underlying FAD cause a gain, not loss, of function.) However, a careful reading of the paper raises concern in this writer's mind that the idea postulated here appears to go beyond the presented data.

    For one, it is not clear that the conditional knockout mice used here have a PS-1 deletion in neural stem or progenitor cells. The paper states that PS-1 is deleted in excitatory neurons of adult mouse forebrain. This raises the question how accumulating APP-CTFs in postmitotic neurons could impair neurogenesis in stem cells and makes the observed 34 percent decrease in enrichment-induced dentate gyrus neurogenesis difficult to interpret. It also raises the question whether these mice are suitable to study neurogenesis.

    For another, the second part of the hypothesis-the role of neurogenesis in clearing outdated memory traces-appears to hinge on a single result that takes up only four lines of text in the results section, and Figure 7d. In this experiment, the authors subjected mice to a fear-conditioning memory test, then placed some in an enriched environment and tested for retention of the initial learned fear memory. All other analyses conducted in the paper, from brain histology and electrophysiological measurements to basic learning and memory function, did not show significant differences between the PS-1 conditional knockout and control mice. An analysis of similar knockout mice published recently (Yu H 2001) did not study neurogenesis but detected a small memory defect."-Gabrielle Strobel, managing editor, ARF.

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