Generation of aberrant sprouting in the adult rat brain by GAP-43 somatic gene transfer

The expression of GAP-43 was modulated genetically in the adult rat nigrost riatal or septohippocampal pathway using recombinant adeno-associated virus (rAAV) vectors incorporating the neuron specific enolase (NSE) promoter an d either a rat GAP-43 cDNA or the corresponding antisense sequence. Bicistr onic expression of green fluorescent protein (GFP) enabled us to evaluate t ransduced neurons selectively. Single injections of rAAV into the substanti a nigra pars compacta (SNc) transduced both dopaminergic and non-dopaminerg ic neurons stably for the 3-month duration of the study. Transduction with the GAP-43 vector in this region: (1) increased GAP-43 mRNA levels 2-fold c ompared to controls; (2) led to GAP-43 immunoreactivity in neuronal perikar ya, axons, and dendrites that was not observed otherwise; and (3) resulted in GAP-43/GFP-positive axons that were traced to the striatum where they fo rmed clusters of aberrant nets. The GAP-43 antisense vector, in contrast, d ecreased neuropil GAP-43 immunoreactivity compared to controls in the SNc. In septum, injections of the GAP-43 expressing vector also caused aberrant clusters of GAP-43 labelled fibers in terminal fields, i.e., fornix and hip pocampus, that were not observed in control tissues. It therefore appears t hat rAAV vectors provide a novel approach for modulating intraneuronal GAP- 43 expression in the adult brain. (C) 1999 Elsevier Science B.V. All rights reserved.