We used a high-titer recombinant adeno-associated virus (rAAV) vector to express WT or mutant human ␣-synuclein in the substantia nigra of adult marmosets. The ␣-synuclein protein was expressed in 90 -95% of all nigral dopamine neurons and distributed by anterograde transport throughout their axonal and dendritic projections. The transduced neurons developed severe neuronal pathology, including ␣-synuclein-positive cytoplasmic inclusions and granular deposits; swollen, dystrophic, and fragmented neuritis; and shrunken and pyknotic, densely ␣-synuclein-positive perikarya. By 16 wk posttransduction, 30 -60% of the tyrosine hydroxylase-positive neurons were lost, and the tyrosine hydroxylase-positive innervation of the caudate nucleus and putamen was reduced to a similar extent. The rAAV-␣-synuclein-treated monkeys developed a type of motor impairment, i.e., head position bias, compatible with this magnitude of nigrostriatal damage. and 2 for a current review). In adult monkeys, MPTP administration induces profound loss of dopamine neurons in the substantia nigra (SN) and motor impairments similar to those seen in idiopathic PD. The MPTP model, however, has two obvious limitations. First, MPTP-induced toxicity is a rapid, single-hit event, resulting in an acute onset of neurodegeneration and neurological symptoms. Second, the MPTP-affected dopamine neurons do not develop the progressive ␣-synucleinopathy (Lewy bodies and Lewy neuritis, in particular) that is the characteristic hallmark of idiopathic PD. There is thus an obvious need for a new primate model of PD where the pathogenetic mechanisms associated with ␣-synuclein (␣-syn) toxicity and nigrostriatal degeneration can be studied in species close to man.Previous studies have shown that the ␣-syn protein is a major component of the intraneuronal protein aggregates (Lewy bodies and Lewy neuritis) that are pathological hallmarks of the disease (3, 4). Moreover, point mutations in the ␣-syn gene have been shown to cause familiar PD (5, 6), suggesting that abnormal processing and͞or function of ␣-syn may trigger the neurodegenerative process. Although ␣-syn is expressed in neurons throughout the nervous system, neurodegeneration in PD is remarkably selective and is most prominent in the dopaminergic neurons of the SN. Recent studies suggest that this selective vulnerability may be due to interaction of ␣-syn with intracellular dopamine, oxidative stress, and dopamine-dependent free radical damage (7-10). This interaction probably explains why dopaminergic neurons are affected by ␣-syn at expression levels that are nontoxic to other types of cells (10-13).These in vitro data raise the possibility of generating transgenic models of PD by overexpression of the ␣-syn protein in the nigrostriatal dopamine neurons. This approach has given promising results in Drosophila (14). Nevertheless, the attempts made so far in mice, by using standard transgenic technology, have been disappointing. In the transgenic mouse strains generated to date, WT or mutated human ␣-syn have b...
The effects of bilateral excitotoxic lesions of 3 major sources of afferents to the ventral striatum (nucleus accumbens) were compared on an open field test of food neophobia allowing the choice between familiar and novel food. Whereas lesions of the basolatera] amygdala and ventral subiculum had qualitatively similar effects to reduce food neophobia (although not affecting the latency to eat), amygdala lesions increased and the ventral subiculum decreased locomotor activity. In contrast, damage to the ventromedial prelimbic prefrontal cortex only affected initial food choice and latency' measures. By comparison, excitotoxic lesions of the nucleus accumbens itself and intra-accumbens infusion of the TV-methyl-D-aspartate (NMDA) receptor antagonist APS increased activity and attenuated food neophobia. Results are discussed in terms of the role of limbic and prefrontal neuronal networks converging in the nucleus accumbens to control different aspects of the behavioral response to novelty.It is now apparent that the functioning of the ventral striatum, including the nucleus accumbens (n. accumbens), is determined by its so-called limbic afferents from the amygdala, hippocampal formation, and prelimbic corlex. Mogcnson (1984) investigated functional interactions between the limbic system and the striatum using a combined electrophysiological and behavioral approach that focused on the control of locomotor activity by output of the n. accumbens, controlled in turn by its limbic input and modulated by the ascending mesolimbic dopamine system. This approach arose from two distinct lines of work: one demonstrating a special role for the n. accumbens in the control of spontaneous and drug-induced locomotor activity, and the other characterizing the role of the limbic system in mediating behavioral and aversive responses to novelty, including aversion and exploration. Thus, dopaminedependent mechanisms of the n. accumbens mediate the locomotor stimulant effect of amphetamine in the rat
The therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) for Parkinson's disease is likely to depend on sustained delivery of the appropriate amount to the target areas. Recombinant adeno-associated viral vectors (rAAVs) expressing GDNF may be a suitable delivery system for this purpose. The aim of this study was to define a sustained level of GDNF that does not affect the function of the normal dopamine (DA) neurons but does provide anatomical and behavioral protection against an intrastriatal 6-hydroxydopamine (6-OHDA) lesion in the common marmoset. We found that unilateral intrastriatal injection of rAAV resulting in the expression of high levels of GDNF (14 ng/mg of tissue) in the striatum induced a substantial bilateral increase in tyrosine hydroxylase protein levels and activity as well as in DA turnover. Expression of low levels of GDNF (0.04 ng/mg of tissue), on the other hand, produced only minimal effects on DA synthesis and only on the injected side. In addition, the low level of GDNF provided ϳ85% protection of the nigral DA neurons and their projections to the striatum in the 6-OHDA-lesioned hemisphere. Furthermore, the anatomical protection was accompanied by a complete attenuation of sensorimotor neglect, head position bias, and amphetamine-induced rotation. We conclude that when delivered continuously, a low level of GDNF in the striatum (approximately threefold above baseline) is sufficient to provide optimal functional outcome.
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