Sub-regional differences and mechanisms of the short-term plasticity of dopamine overflow in striatum in mice lacking alpha-synuclein

Mice lacking the pre-synaptic protein alpha-synuclein (α-syn) demonstrate enhanced facilitation of dopamine (DA) overflow in dorsal striatum following repeated, high-frequency burst stimulation of the dopaminergic pathways. Dorsal striatum is most vulnerable to neurodegeneration in Parkinson's disease. The role of α-syn in facilitation of DA overflow in the ventral striatum, which is less vulnerable to neurodegeneration, is unknown. We investigated the link between the absence of α-syn and the plasticity of DA overflow in the dorsal and ventral striatum by in vivo voltammetry and the possible mechanisms of modulation of the plasticity of DA overflow. We show that the facilitation of DA overflow following paired-burst stimulation is significantly enhanced in the dorsolateral but not in the ventral striatum of mice lacking α-syn. Re-uptake inhibitor, GBR12909, completely eliminated the facilitation of DA overflow regardless of the presence of α-syn in both dorsal and ventral striatum, indicating that re-uptake is critical for maintenance of paired-burst facilitation (PBF). Inhibition of D2 autoreceptors by haloperidol decreased PBF only in mice lacking α-syn. However, the basal function of D2 autoreceptors tested by paired-pulse depression of DA overflow was not different between the lines. Therefore, alterations in the D2 autoreceptor system do not explain the different effect of haloperidol on PBF in mice with and without α-syn. This indicates that neither re-uptake nor D2 autoreceptors differentiate the PBF between the genotypes. We propose that modification of DA vesicles in α-syn knockout mice, as reported in several studies, may be a factor underlying the enhanced PBF in these mice.

► Paired-burst stimulation facilitates dopamine overflow (PBF) in mouse striatum.
► There is α-syn dependent heterogeneity of the expression of PBF in striatum.
► Dorsolateral but not ventral striatum is affected by the absence of α-syn.
► Sub-regional alteration in PBF is not mediated by dopamine transporter or D2 autoreceptor.
► Re-uptake is critical for the expression of PBF in striatum.