Research Paper Volume 13, Issue 16 pp 20319—20334

Inhibition of endoplasmic reticulum stress reverses synaptic plasticity deficits in striatum of DYT1 dystonia mice

ER stress inhibitor rescues long-term memory deficit in Tor1a+/- mice. (A) Time-course of striatal LTD expression in SPNs from Tor1a+/+ and Tor1a+/- mice. After in vivo treatment with TUDCA, the HFS protocol induced striatal LTD expression in Tor1a+/- mice. (B) Time-course of striatal LTP expression in SPNs from Tor1a+/+ and Tor1a+/- mice. LTP amplitude in Tor1a+/- mice was comparable to that of SPNs from Tor1a+/+ littermates. (C) Summary plot of NMDA/AMPA current ratio calculated in SPNs from Tor1a+/+ and Tor1a+/- mice. treatment with TUDCA normalized the NMDAR/AMPAR ratio in Tor1a+/- mice (P>0.05). (D) AMPAR-mediated currents recorded at different HP in Tor1a+/+ and Tor1a+/- SPNs. The IV curve of AMPAR-EPSC also revealed no significant difference between genotypes (P>0.05). (E) Representative images showed spine morphology of Tor1a+/- and Tor1a+/+ SPNs. (F–H) Histogram representing the quantification of dendritic spine density (F), dendritic spine size (G, spine length and head width) and dendritic spine type (H, mushroom, stubby, thin) in Tor1a+/- and Tor1a+/+ SPNs. (I) Representative confocal images from two SPNs recorded in Tor1a+/- and Tor1a+/+ slices after treatment of TUDCA (scale bar: 10 μm). Recording electrodes were filled with biocytin (pink) and SPNs were immunolabelled with anti-ENK (green) and anti-DARPP-32 (red). (J) WB analysis for p-GluA1 (Ser845), GluA1, GluA2, NMDAR2A, NMDAR2B, PSD-95 and α-tubulin in striatum tissues of Tor1a+/- and age-matched Tor1a+/+ mice after treatment of TUDCA. (K) Histogram shows the quantification of protein levels following normalization on α-tubulin in Tor1a+/- and age-matched Tor1a+/+ mice. In each group, five mice were used (N=5), and three independent electrophysiological recordings or experiments were conducted for each mouse (n=3). P

Figure 4. ER stress inhibitor rescues long-term memory deficit in Tor1a+/- mice. (A) Time-course of striatal LTD expression in SPNs from Tor1a+/+ and Tor1a+/- mice. After in vivo treatment with TUDCA, the HFS protocol induced striatal LTD expression in Tor1a+/- mice. (B) Time-course of striatal LTP expression in SPNs from Tor1a+/+ and Tor1a+/- mice. LTP amplitude in Tor1a+/- mice was comparable to that of SPNs from Tor1a+/+ littermates. (C) Summary plot of NMDA/AMPA current ratio calculated in SPNs from Tor1a+/+ and Tor1a+/- mice. treatment with TUDCA normalized the NMDAR/AMPAR ratio in Tor1a+/- mice (P>0.05). (D) AMPAR-mediated currents recorded at different HP in Tor1a+/+ and Tor1a+/- SPNs. The IV curve of AMPAR-EPSC also revealed no significant difference between genotypes (P>0.05). (E) Representative images showed spine morphology of Tor1a+/- and Tor1a+/+ SPNs. (FH) Histogram representing the quantification of dendritic spine density (F), dendritic spine size (G, spine length and head width) and dendritic spine type (H, mushroom, stubby, thin) in Tor1a+/- and Tor1a+/+ SPNs. (I) Representative confocal images from two SPNs recorded in Tor1a+/- and Tor1a+/+ slices after treatment of TUDCA (scale bar: 10 μm). Recording electrodes were filled with biocytin (pink) and SPNs were immunolabelled with anti-ENK (green) and anti-DARPP-32 (red). (J) WB analysis for p-GluA1 (Ser845), GluA1, GluA2, NMDAR2A, NMDAR2B, PSD-95 and α-tubulin in striatum tissues of Tor1a+/- and age-matched Tor1a+/+ mice after treatment of TUDCA. (K) Histogram shows the quantification of protein levels following normalization on α-tubulin in Tor1a+/- and age-matched Tor1a+/+ mice. In each group, five mice were used (N=5), and three independent electrophysiological recordings or experiments were conducted for each mouse (n=3). P<0.05 was considered to be statistically significant.