Presenilin 1 (PS1) and PS2 play an essential role in neurogenesis during development. Moreover, we recently found a significant deficit in neurogenesis in the adult brain of forebrain-specific PS1 knockout mice following environmental enrichment and a significant implication for newly generated neurons in memory processing (formation). However, due to the inability of simultaneously inactivating PS2 expression, we speculate that the full extent of phenotypes may not be disclosed, as compensation by PS2 may occur in these PS1 knockout mice. Furthermore, since the knockout of PS1 was neither inducible nor reversible, we were unable to specifically study the functional consequences of neurogenesis in a temporal-association manner, which is a fundamental way to study the association of newly generated neurons with behavioral responses. Therefore, it is particularly important to generate more advanced presenilin mutant models for the further identifying the role for presenilin, and especially for PS1, in adult neurogenesis as well as determining the functional consequences of neurogenesis at the cognitive behavioral levels such as learning and memory. Accordingly, the specific aims of this proposal are: (1) To generate PS1 and PS2 (double) knockout mice. This will be achieved by combining both forebrain-specific PS1 knockout mice with conventional PS2 knockout mice. (2) To determine the overall role for both PS1 and PS2 in adult neurogenesis. We will carefully and systematically evaluate these overall roles in both normal settings and after environmental enrichment using multiple-staining approaches. (3) To generate forebrain-specific inducible/reversible PS1 knockout and FAD-linked mutant PS1 knock-in mice. We will use our established Cre/IoxP-tTA/tetO gene manipulation system to produce these two mutant mouse strains. (4) To further determine the role for PS1 and the mutant PS1 in neurogenesis in the adult brain. Neurogenesis during both aging and enrichment will be systematically assessed by using the multiplestaining approaches. (5) To study the functional consequences of adult neurogenesis. In our system, PS1 can be used as a genetic switch for adult neurogenesis and thus, by regulating PS1 expression, we are able to temporally associate and study neurogenesis with behavioral processes. We will focus on learning and memory. Our studies should provide insights into PS1 and mutant PS1 functions, the molecular mechanisms of neurogenesis in the adult brain, and the functional significance of adult neurogenesis in learning and memory.
