Fig. 3: Ulotaront and selective TAAR1 agonist RO5166017 bidirectionally modulate the amplitude of evoked EPSC in putative D2 MSNs.
Schematic of the mouse line (A, top), brain area (A, bottom) and recording strategy (B). Evoked EPSCs were elicited by stimulation of the deep cortical layer and recorded in D1-non-expressing (tdTom-) MSNs using whole-cell V-clamp configuration, with bicuculline (BIC) added into the aCSF. C−H Effect of ulotaront on evEPSC in putative D2-expressing MSNs. C Experimental time course. Evoked EPSC amplitude was analyzed during pre-drug baseline condition and for the last 3 min of treatment with 10 μM ulotaront or vehicle. D Representative average traces of evEPSCs before and during vehicle (top) and ulotaront application (bottom), as well as upon perfusion with of 10 μM NBQX. E Amplitude during baseline condition and upon bath application of ulotaront. F Comparison of the normalized-to-baseline evEPSC amplitude for vehicle- vs ulotaront-treated groups, at the level of mean and variance (average mean and standard deviation are presented in parentheses). G Individual data (bottom) and count histogram (top) of the normalized amplitude for vehicle (left) and ulotaront (right) groups. The histogram is overlaid by the optimal Gaussian mixture model (number of components k = 1 and k = 2 for vehicle and ulotaront groups, respectively; see Table S1) and the individual values were color-coded based on a cluster analysis run on the distribution model (see Supplementary Materials and Methods). Inset, plot of the Bayes information criterion (BIC) generated for the Gaussian mixture models with k components. H Average time course of the normalized evEPSC amplitude. The ulotaront data is presented as a single group, and also split into the two clusters found in G. I Analysis of vehicle vs ulotaront groups after the cells were clustered based on the direction of the change relative to baseline; decrease (left, < 100%baseline) and increase (right, > 100%baseline). J−M Effect of 2 μM RO5166017 (RO-017) on evEPSC, corresponding to (C), (E), (F), (H) and (I). In (L) and (M), cells were grouped based on the direction of the effect; decrease (M top, <100%baseline) and increase (M bottom, >100%baseline) relative to baseline. Data are mean ± s.e.m. Each dot represents a cell (n = 7−24), except in the average time course (H, L). Statistics are described in Table S1. ns, not significant; *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.
