The underlying basis for cognitive impairment in psychiatric and much neurologic disease is obscure. Abnormal synaptic networks arising from developmental and/or adult perturbations may be the pathophysiological substrate for cognitive impairment. At the level of individual cellular components of the network we can study molecules that are important for its establishment and maintenance. Moreover, with newer molecular genetic tools we can more precisely dissect the contribution of particular molecules to these processes. Nerve growth factor (NGF), the prototypic neurotrophin, has been well established in the peripheral nervous system, where its function as a target derived factor is essential for the development and survival of sympathetic and a subpopulation of sensory neurons. In the central nervous system (CNS), NGF is implicated in modulating cognition through its stimulatory effect on the septohippocampal cholinergic pathway, as suggested by pharmacological studies involving infusion of NGF or blocking antibodies. To explore the cellular basis for this cognitive effect in mouse and define the relationship between neurons synthesizing and those responding to NGF in the hippocampus, we have developed a somatic genetic mosaic approach. A binary gene system employing the bacteriophage P1 derived cre/loxP recombinant system provides a method to create somatic tissues in which some cells differ from their neighbors by a single gene's activation, producing a gain of NGF function. With our approach a germline transmitted NGF transgene is flanked by loxP elements (cis recombinant elements) that are activated to recombine by the somatic expression of the cre recombinase gene delivered by a viral vector. This affords temporal and spatial control of recombination and the ability to regulate the number of activated cells within a mosaic tissue. We have constructed multiple lines of transgenic mice harboring an NGF excision activation transgene (XAT) that produces a gain of function when activated by a herpes simplex amplicon vector that expresses cre recombinase (HSVcre). The studies proposed herein utilize the conditional NGF gain of function mice to investigate the role of NGF in septohippocampal cholinergic function. These studies will reveal much new information regarding the function of NGF in the adult nervous system. Moreover, continued refinement of the somatic mosaic approach will likely lead to its broad application to study the function of other genes in the intact CNS.
