Nigral injection of antisense oligonucleotides to synaptotagmin I using HVJ-liposome vectors causes disruption of dopamine release in the striatum and impaired skill learning.
ABSTRACT To produce an animal model of a dopa-responsive motor disorder with depletion of dopamine (DA) release in the striatum by dysfunction of the transmitter release machinery of the nigrostriatal DA system, we performed an intra-nigral injection of an HVJ-liposome gene transfer vector containing antisense oligodeoxynucleotides (ODNs) against synaptotagmin I (SytI), a key regulator of Ca(2+)-dependent exocytosis and endocytosis in adult rats. A unilateral intra-nigral injection of HVJ-liposome vectors containing antisense ODNs against SytI (syt-AS) caused a moderate disruption of methamphetamine-induced release of DA in the treated side of the striatum, while the syt-AS treatment did not affect physiological release of DA in the treated striatum. A bilateral intra-nigral injection of HVJ-liposome vectors containing syt-AS induced an impairment of the striatal DA-mediated acquisition of skilled behavior in a rotarod task without any deficits in general motor functions, such as spontaneous locomotor activity, motor adjusting steps, equilibrium function, or muscle strength. These findings suggest that an intra-nigral treatment with HVJ-liposome vectors containing syt-AS may cause a long-lasting nigral knockdown of SytI which, in turn, leads to a moderate dysfunction of the DA release machinery in the terminals of the nigrostriatal DA system and a subsequent mild depletion of DA release in the striatum.
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ABSTRACT: Long-term treatment with the dopamine precursor levodopa (L-DOPA) induces dyskinesia in Parkinson's disease (PD) patients. We divided hemiparkinsonian rats treated chronically with L-DOPA into two groups: one showed motor improvement without dyskinesia, and the other developed debilitating dyskinesias in response to the treatment. We then compared the plasticity of corticostriatal synapses between the two groups. High-frequency stimulation of cortical afferents induced long-term potentiation (LTP) of corticostriatal synapses in both groups of animals. Control and non-dyskinetic rats showed synaptic depotentiation in response to subsequent low-frequency synaptic stimulation, but dyskinetic rats did not. The depotentiation seen in both L-DOPA-treated non-dyskinetic rats and intact controls was prevented by activation of the D1 subclass of dopamine receptors or inhibition of protein phosphatases. The striata of dyskinetic rats contained abnormally high levels of phospho[Thr34]-DARPP-32, an inhibitor of protein phosphatase 1. These results indicate that abnormal information storage in corticostriatal synapses is linked with the development of L-DOPA-induced dyskinesia.Nature Neuroscience 06/2003; 6(5):501-6. · 15.25 Impact Factor
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ABSTRACT: Research on the basal ganglia suggests that they are critically involved in building up sequences of behavior into meaningful, goal-directed repertoires. Work on rodents, monkeys and humans suggests that the basal ganglia act as part of a distributed forebrain system that helps to encode such repertoires through behavioral learning, and that is engaged in the expression of such repertoires once they have been internalized. The basal ganglia also may be critical to the expression of innate behavioral routines. Experimental findings on reward-based learning suggest that neural activity in the striatum and substantia nigra, pars compacta changes during behavioral learning. New evidence also suggests extreme specificity in the neural connections interrelating the basal ganglia, cerebral cortex and thalamus. Adaptive control of behavior may centrally depend on these circuits and the evaluator-reinforcement circuits that modulate them.Current Opinion in Neurobiology 01/1996; 5(6):733-41. · 7.34 Impact Factor
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ABSTRACT: Synaptotagmin is a synaptic vesicle protein implicated in neurotransmitter release. Molecular characterization of four mutant alleles of this protein in Drosophila melanogaster has permitted an investigation of synaptotagmin's role in synaptic physiology and of some of the structural requirements for its function. Reduced levels of synaptotagmin resulted in a substantial alteration in synaptic function in the eye and at larval neuromuscular junctions. Decreased neurotransmitter release caused smaller evoked synaptic potentials. However, the frequency, but not the size, of spontaneous quantal events was simultaneously increased. These abnormalities do not appear to be secondary to a detectable morphological change in the arborization of the synapse. The increased frequency of spontaneous events was insufficient to deplete significantly the vesicle supply and thereby account for reduced transmission. These data are discussed in the context of models in which synaptotagmin's function includes a role in vesicle docking.Neuron 05/1994; 12(4):909-20. · 15.77 Impact Factor