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Fig. 4 | Acta Neuropathologica Communications

Fig. 4

From: In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition

Fig. 4

Analyses of firing-pattern and intrinsic firing properties of NAS-, AST-derived neurons, WT mouse dopamine neurons, and mouse dopamine neurons overexpressing α-synuclein. The experiments and analyses were performed in parallel via a blinded experimental design. a left: Interspike interval (ISI) distribution in NAS-derived dopamine neurons. Each curve in individual panels represents cumulative probability for an individual neuron, the 50% probability was below 1 s. Right: ISI distribution in AST-derived dopamine neurons, the 50% probability was below 0.25 s. b Left: ISI distribution of WT mouse dopamine neurons, the 50% probability was below 2 s. Right: ISI distribution observed in mouse dopamine neurons overexpressing α-synuclein. The 50% probability was below 0.5 s. c Left: Instantaneous frequency distribution obtained from NAS-derived neurons; the 50% probability was below 10 Hz. Right: Instantaneous frequency distribution obtained from AST-derived neurons; the 50% probability was below 20 Hz. d Left: Instantaneous frequency distribution of WT mouse dopamine neurons, the 50% probability was below 5 Hz. Right: Instantaneous frequency distribution of mouse dopamine neurons overexpressing α-synuclein, the 50% probability was below 10 Hz. e Mean firing frequency (Hz) against percentage of spike within a burst (%SWB) for NAS- and AST-derived dopamine neuron groups. Inset shows increased α-synuclein in the neurons enhanced %SWB in both iPSC-derived human-like dopamine neurons and mouse dopamine neurons. f Mean firing frequency against %SWB for WT mouse dopamine neurons, and mouse overexpressing α-synuclein. g and h Mean firing frequency against up-state for NAS- and AST-derived dopamine neurons, or WT mouse dopamine neurons against mouse dopamine neurons overexpressing α-synuclein. Inset shows a higher amplitude of up-state in both AST-derived dopamine neurons and mouse dopamine neurons overexpressing α-synuclein. I. The spike half-width of AST-derived dopamine neurons (n = 16) is shorter than NAS-derived neurons (n = 12, F(3, 65) = 3.744, p = 0.015, one-way ANOVA). j The spike half-amplitude of AST-derived neurons is higher than NAS-derived neurons (F(3, 65) = 4.681, p = 0.005, one-way ANOVA). k interspike intervals are calculated over 1 min of spontaneous firing activity, the coefficients of variation of the interspike interval are significantly larger in either AST-derived dopamine neurons or mouse dopamine neurons overexpressing α-synuclein compared to NAS-derived dopamine neurons or WT mouse dopamine neurons (F(3, 63) = 21.39, P < 0.0001. one-way ANOVA). l Compared to NAS-derived dopamine neurons or WT mouse dopamine neurons, the spontaneous firing rates are higher in AST-derived dopamine neurons or mouse dopamine neurons overexpressing α-synuclein (F(3, 65) = 10.67, P < 0.0001, one-way ANOVA). m Compared to their counterpart experimental group, the percentage of spike within a burst is higher in AST-derived dopamine neurons or mouse dopamine neurons overexpressing α-synuclein (F(3, 67) = 160.8, P < 0.0001, one-way ANOVA). n The up-state is significantly higher in either AST-derived dopamine neurons or mouse dopamine neurons overexpressing α-synuclein, compared to their counterpart experimental groups containing endogenous α-synuclein level (F(3, 67) = 34.57, P < 0.0001, one-way ANOVA)

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