Sequential administration of GDNF into the substantia nigra and striatum promotes dopamine neuron survival and axonal sprouting but not striatal reinnervation or functional recovery in the partial 6-OHDA lesion model

Glial cell line-derived neurotrophic factor (GDNF) has prominent survival-p romoting effects on lesioned nigrostriatal dopamine neurons, but understand ing of the conditions under which functional recovery can be obtained remai ns to be acquired. We report here the time course of nigrostriatal axon deg eneration in the partial lesion model of Parkinson's disease and the morpho logical and functional effects of sequential administration of GDNF in the substantia nigra (SN) and striatum during the first 5 weeks postlesion. By 1 day postlesion, the nigrostriatal axons had retracted back to the level o f the caudal globus pallidus. Over the next 6 days axonal retraction progre ssed down to the SN, and during the following 7 weeks 74% of tyrosine hydro xylase-positive (TH+) and 84% of retrogradely labeled nigral neurons were l ost, with a more pronounced loss in the rostral part of the SN. GDNF admini stration protected 70 and 72% of the nigral TH+ and retrogradely labeled ce ll bodies, respectively, but did not prevent the die-back of the lesioned n igrostriatal axons. Although clear signs of sprouting were observed close t o the injection site in the striatum as well as in the globus pallidus, the overall DA innervation of the striatum [as measured by [H-3]-N-[1-(2-benzo (b)thiopenyl) cyclohexyl]piperidine-binding autoradiography] was not improv ed by the GDNF treatment. Moreover, the lesion-induced deficits in forelimb akinesia and drug-induced rotation were not attenuated. We conclude that f unctional recovery in the partial lesion model depends not only on preserva tion of the nigral cell bodies, but more critically on the ability of GDNF to promote significant reinnervation of the denervated striatum, (C) 2000 A cademic Press.