Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human α-synuclein

Hatos Center, University of California Los Angeles, Los Angeles, California, USA.
Journal of Neuroscience Research (Impact Factor: 2.59). 07/2011; 89(7):1091-102. DOI: 10.1002/jnr.22611
Source: PubMed


Overexpression or mutation of α-synuclein (α-Syn), a protein associated with presynaptic vesicles, causes familial forms of Parkinson's disease in humans and is also associated with sporadic forms of the disease. We used in vivo microdialysis, tissue content analysis, behavioral assessment, and whole-cell patch clamp recordings from striatal medium-sized spiny neurons (MSSNs) in slices to examine dopamine transmission and dopaminergic modulation of corticostriatal synaptic function in mice overexpressing human wild-type α-Syn under the Thy1 promoter (α-Syn mice). Tonic striatal extracellular dopamine and 3-methoxytyramine levels were elevated in α-Syn mice at 6 months of age, prior to any reduction in total striatal tissue content, and were accompanied by an increase in open-field activity. Dopamine clearance and amphetamine-induced dopamine efflux were unchanged. The frequency of MSSN spontaneous excitatory postsynaptic currents (sEPSCs) was lower in α-Syn mice. Amphetamine reduced sEPSC frequency in wild types (WTs) but produced no effect in α-Syn mice. Furthermore, whereas quinpirole reduced and sulpiride increased sEPSC frequency in WT mice, they produced the opposite effects in α-Syn mice. These observations indicate that overexpression of α-Syn alters dopamine efflux and D2 receptor modulation of corticostriatal glutamate release at a young age. At 14 months of age, the α-Syn mice presented with significantly lower striatal tissue dopamine and tyrosine hydroxylase content relative to WT littermates, accompanied by an L-DOPA-reversible sensory motor deficit. Together, these data further validate this transgenic mouse line as a slowly progressing model of Parkinson's disease and provide evidence for early dopamine synaptic dysfunction prior to loss of striatal dopamine.

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Available from: Wendy Walwyn, Aug 04, 2014
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    • "The open field test was shown to have high power to detect drug effect; at 7 months of age, less than 10 mice are needed to detect a 50% reduction in distance travelled , time spent in motion and movement velocity, with 80% power (Lam et al. 2011). Spontaneous activity in an open field (25.5 9 25.5 cm) was monitored for 15 min using an automated system (Truscan system for mice; Coulbourn Instruments, Allentown , PA). "
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    ABSTRACT: Genome-wide association studies have identified strong associations between the risk of developing Parkinson's disease (PD) and polymorphisms in the genes encoding α-synuclein and the microtubule-associated protein tau. However, the contribution of tau and its phosphorylated form (p-tau) to α-synuclein-induced pathology and neuronal dysfunction remains controversial. We have assessed the effects of NAP (davunetide), an eight-amino acid peptide that decreases tau hyperphosphorylation, in mice overexpressing wild-type human α-synuclein (Thy1-aSyn mice), a model that recapitulates aspects of PD. We found that the p-tau/tau level increased in a subcortical tissue block that includes the striatum and brain stem, and in the cerebellum of the Thy1-aSyn mice compared to nontransgenic controls. Intermittent intranasal NAP administration at 2 μg/mouse per day, 5 days a week, for 24 weeks, starting at 4 weeks of age, significantly decreased the ratio of p-tau/tau levels in the subcortical region while a higher dose of 15 μg/mouse per day induced a decrease in p-tau/tau levels in the cerebellum. Both NAP doses reduced hyperactivity, improved habituation to a novel environment, and reduced olfactory deficits in the Thy1-aSyn mice, but neither dose improved the severe deficits of motor coordination observed on the challenging beam and pole, contrasting with previous data obtained with continuous daily administration of the drug. The data reveal novel effects of NAP on brain p-tau/tau and behavioral outcomes in this model of synucleinopathy and suggest that sustained exposure to NAP may be necessary for maximal benefits.
    10/2014; 2(5). DOI:10.1002/prp2.65
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    • "A short-term intranasal administration of the microtubule-interacting peptide in Thy1-hSNCA140 mice led to improvement in motor function and reduction of ␣-synuclein inclusions, pointing to the essential function of microtubule system and a potentially important therapeutic target in PD (Fleming et al., 2011). Overexpression of WT hSNCA140 altered DA efflux and D2 receptor modulation of corticostriatal glutamate release in Thy1-hSNCA mice at early ages, which preceded DA and TH loss in the striatum, showing a slowly progression model of PD (Lam et al., 2011). In transgenic mice overexpressing hSNCA under the Thy1 promoter, most hSNCA transcripts (SNCA140, SNCA126, SNCA112, SNCA98) were elevated in a region-specific manner when compared to WT mice, consistent with the region-specific hSNCA transcripts level abnormalities in PD patients (McLean et al., 2012). "
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    ABSTRACT: Parkinson disease (PD; MIM 168600) is the second most common progressive neurodegenerative disorder characterized by a variety of motor and non-motor features. To date, at least 20 loci and 15 disease-causing genes for parkinsonism have been identified. Among them, the α-synuclein (SNCA) gene was associated with PARK1/PARK4. Point mutations, duplications and triplications in the SNCA gene cause a rare dominant form of PD in familial and sporadic PD cases. The α-synuclein protein, a member of the synuclein family, is abundantly expressed in the brain. The protein is the major component of Lewy bodies and Lewy neurites in dopaminergic neurons in PD. Further understanding of its role in the pathogenesis of PD through various genetic techniques and animal models will likely provide new insights into our understanding, therapy and prevention of PD.
    Ageing research reviews 04/2014; 15(1). DOI:10.1016/j.arr.2014.04.002 · 4.94 Impact Factor
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    • "A strong rostrocaudal TH gradient was found in both WT and ASO mice, with caudal sections showing weaker TH staining (location: F 9,144 42.7, P 0.0001). Our finding that there is no significant nigrostriatal dopamine denervation is consistent with previous reports showing that striatal TH immunoreactivity is intact until 14 mo of age in these animals (Chesselet et al. 2012; Lam et al. 2011). "
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    ABSTRACT: Numerous studies have suggested that alpha-synuclein plays a prominent role in both familial and idiopathic Parkinson's disease (PD). Mice in which human alpha-synuclein are over-expressed (ASO) display progressive motor deficits and many non-motor features of PD. However, it is unclear what in vivo pathophysiological mechanisms drive these motor deficits. It is also unknown whether previously proposed pathophysiological features (i.e. increased beta oscillations, bursting and synchronization) described in toxin-based, nigrostriatal dopamine-depletion models are also present in ASO mice. To address these issues, we first confirmed that 5-6 months old ASO mice have robust motor dysfunction, despite no significant nigrostriatal dopamine degeneration. In the same animals, we then recorded simultaneous single-units and local field potentials (LFP) in the substantia nigra pars reticulata (SNpr), the main basal ganglia output nucleus, and one of its main thalamic targets, the ventromedial nucleus, as well as LFPs in the primary motor cortex in anesthetized ASO mice and their age-matched, wild-type littermates. Neural activity was examined during slow wave activity and desynchronized cortical states, as previously described in 6-hydroxydopamine-lesioned rats. In contrast to toxin-based models, we found a small decrease, rather than an increase, in beta oscillations in the desynchronized state. Similarly, synchronized burst firing of nigral neurons observed in toxin-based models was not observed in ASO mice. Instead, we found more subtle changes in pauses of SNpr firing compared to wild-type controls. Our results suggest that the pathophysiology underlying motor dysfunction in ASO mice is distinctly different from striatal dopamine depletion models of parkinsonism.
    Journal of Neurophysiology 09/2013; 110(12). DOI:10.1152/jn.00441.2013 · 2.89 Impact Factor
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