Nerve growth factor somatic mosaicism produced by herpes virus-directed expression of cre recombinase

Focal molecular genetic alteration of the intact mammalian brain will be required to elucidate gene product function in cells comprising synaptic networks. To this end, a somatic mosaic approach has been developed for the mouse whereby a dormant germline transgene is activated by the somatic delivery and expression of cre recombinase. Transgenic mice harboring a recombinational substrate, the germline-transmitted nerve growth factor excision activation transgene (NGF-XAT) were generated. Somatic delivery of virus vectors expressing cre recombinase into the brain of NGF-XAT mice resulted in regional recombination and activation of the transgene as demonstrated at the DNA level by PCR and at the protein level by both immunocytochemistry and ELISA. This approach has been used to evaluate a behavioral correlate of unilateral NGF mosaicism within the dorsal hippocampal formation. NGF-XAT mice activated by expression of cre recombinase manifest increased locomotor activity compared with NGF-XAT mice transduced by a control virus expressing Escherichia coli beta-galactosidase. These data indicate that focally increased expression of NGF in one part of a synaptic network can elicit changes in behavior presumably by altering the overall function of NGF-responsive neural circuitry. This approach should have broad application to other gene products and promises to provide the unprecedented ability to create and study discrete genetic modifications in the context of an intact adult mammal.