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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- "However, evidence indicates that motor-skill learning, another form of procedural learning , is also dependent on normal function of the sensorimotor striatum . For example, moderate loss of dopamine   or deletion of NMDA receptors  in the striatum impaired skill learning in a rotarod task. Also, our previous findings show that blockade of striatal D1 dopamine receptors during training prevents the acquisition of a motor skill in a running-wheel paradigm . "
ABSTRACT: The sensorimotor striatum is important for procedural learning, including skill learning. Our previous findings indicate that this part of the striatum mediates the acquisition of a motor skill in a running-wheel task and that this skill learning is dependent on striatal D1 dopamine receptors. Here, we investigated whether the sensorimotor striatum is also involved in the consolidation of this skill memory and whether this consolidation is modified by the indirect dopamine receptor agonist cocaine. Rats were trained on a running wheel for 2 days (40 min/day) to learn a new motor skill, that is, the ability to control the movement of the wheel. Before each training session, the animals received an injection of vehicle or cocaine (25 mg/kg, i.p.). Immediately following the training session, an intrastriatal infusion of 2% lidocaine (1 μl) or a sham infusion were administered. Wheel-skill performance was tested before and repeatedly after the training. Our results show that post-trial intrastriatal infusion of lidocaine disrupted late-stage long-term skill memory (post-training days 6–26), but spared early long-term memory (1 day after the training). Skill consolidation was more susceptible to such disruption in animals that practiced less during the training. Cocaine given pre-trial prevented this post-trial disruption of skill consolidation. These findings indicate that the sensorimotor striatum is critical for the consolidation of late but not early long-term skill memory. Furthermore, cocaine appeared to stabilize motor-memory formation by protecting consolidation processes after the training.Behavioural brain research 04/2009; 199(1-199):103-107. DOI:10.1016/j.bbr.2008.07.010 · 3.39 Impact Factor
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ABSTRACT: Excitotoxic lesion of the striatum provides a useful model for evaluating the excitotoxic processes involved in neurological disorders, in particular stroke diseases. The behavioural outcome after such injury is however poorly described. We have therefore investigated the potential behavioural deficits induced by a NMDA-induced excitotoxic unilateral lesion of the lateral part of the striatum, by comparison with a PBS striatal injection (sham procedure), and non-operated mice behaviour. Three groups of male adult Swiss mice were constituted: unilateral NMDA (20 nmol striatal NMDA injection), sham (striatal PBS injection), and control (healthy non-operated mice). From 14 to 29 days post-surgery, sensorimotor and mnesic tests were performed in all groups. After euthanasia, immunohistochemical stainings (NeuN and GFAP) were performed in order to assess the size of the lesion. Straight runway and passive avoidance performances revealed mild deficits related to the excitotoxic NMDA-induced lesion as compared to the sham procedure. Moreover, accelerated rotarod and Morris water maze acquisition performances also revealed deficits related to the surgery, i.e. observed in sham-operated as compared to control mice. NeuN staining revealed no striatal lesion in the sham and non-operated groups in contrast to the NMDA-injected group in which the volume of infarcted striatum was 2.4+/-0.3mm3. GFAP staining revealed a glial reaction in the lesioned striatum of NMDA animals and at the PBS injection site in sham animals. These results suggest that NMDA-induced excitotoxic lesion induces subtle long-term behavioural deficits in mice. Moreover, this study shows the importance of the sham group to investigate the behavioural deficits after excitotoxic lesion models in mice.Behavioural Brain Research 04/2007; 178(2):235-43. DOI:10.1016/j.bbr.2006.12.023 · 3.39 Impact Factor