Nigral injection of antisense oligonucleotides to synaptotagmin I using HVJ-liposome vectors causes disruption of dopamine release in the striatum and impaired skill learning

ArticleinBrain Research 1095(1):178-89 · July 2006with8 Reads
DOI: 10.1016/j.brainres.2006.04.039 · Source: PubMed
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.
    • "Thus, dopamine receptor agonists infused into the striatum modified procedural maze learning ( Packard and White, 1991 ; Packard et al., 1994 ). Conversely, moderate striatal dopamine depletion impaired skill learning in a rotarod task ( Ogura et al., 2005 ; Akita et al., 2006 ). What molecular mechanisms in the striatum mediate procedural learning and where do they occur? "
    [Show abstract] [Hide abstract] ABSTRACT: This chapter demonstrates that psychostimulants alter the expression of perhaps hundreds of genes in the cortex and the basal ganglia. These include effector genes such as those encoding neuropeptide transmitters that modulate basal ganglia circuit activity in several nuclei, but also transcription factors that regulate the expression of other genes, as well as a variety of other neuroplasticity-related molecules. The findings of numerous studies show that, in the striatum, psychostimulants affect gene regulation predominantly in neurons that give rise to the direct striatal output pathway, with lesser to minimal molecular effects in the indirect pathway. The chapter reviews that the relative impact on these two pathways is to some degree dependent on cortex-activating contextual variables. For the last two decades, much effort in addiction research has been devoted to understanding the significance of molecular changes in motivation-related striatal domains. However, molecular imaging studies demonstrate that psychostimulant-induced gene regulation is considerably more pronounced in associational and, especially, sensorimotor corticostriatal domains. It concludes that Future work will have to determine the functional consequences of such changes in these latter domains. However, studies indicate that these molecular changes occur in striatal areas associated with switching functions, procedural learning and compulsion. They may thus underlie aberrant habit formation and compulsive behavior that signify drug addiction.
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    • "However, evidence indicates that motor-skill learning, another form of procedural learning [38], is also dependent on normal function of the sensorimotor striatum [25]. For example, moderate loss of dopamine [1,24] or deletion of NMDA receptors [7] 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 [45]. "
    [Show abstract] [Hide abstract] 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.
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    • "Given the absence of overt morphological abnormalities in R552H heterozygous brains, we used electrophysiology to assess functional properties of striatal and cerebellar neurons from these animals. For assessment of striatal function, we recorded evoked field potentials from the dorsolateral striatum, a region previously implicated in skill learning on the accelerating rotarod161718. The input-output function—reflecting the amplitude of the evoked population spike in relation to the stimulation strength—was similar between R552H heterozygotes and wildtype littermates (Figure 3A). "
    [Show abstract] [Hide abstract] ABSTRACT: The most well-described example of an inherited speech and language disorder is that observed in the multigenerational KE family, caused by a heterozygous missense mutation in the FOXP2 gene. Affected individuals are characterized by deficits in the learning and production of complex orofacial motor sequences underlying fluent speech and display impaired linguistic processing for both spoken and written language. The FOXP2 transcription factor is highly similar in many vertebrate species, with conserved expression in neural circuits related to sensorimotor integration and motor learning. In this study, we generated mice carrying an identical point mutation to that of the KE family, yielding the equivalent arginine-to-histidine substitution in the Foxp2 DNA-binding domain. Homozygous R552H mice show severe reductions in cerebellar growth and postnatal weight gain but are able to produce complex innate ultrasonic vocalizations. Heterozygous R552H mice are overtly normal in brain structure and development. Crucially, although their baseline motor abilities appear to be identical to wild-type littermates, R552H heterozygotes display significant deficits in species-typical motor-skill learning, accompanied by abnormal synaptic plasticity in striatal and cerebellar neural circuits.
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