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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    • "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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