Journal: Neurobiology of disease

Article Title: Selective impairment of long-term depression in accumbal D1R+ MSNs involves calcium-permeable AMPARs in early Alzheimer's disease

doi: 10.1016/j.nbd.2026.107568

Figure Lengend Snippet: mGluR-dependent LTD is selectively impaired in D1R+ MSNs, and residual synaptic transmission is selectively NASPM-sensitive in the NAc core of 6-month-old APP/PS1 mice. (A) Schematic representation of whole-cell voltage-clamp recordings of AMPAR-mediated eEPSCs in NAc core MSNs from 6-month-old WT;D1-tdTomato and APP/PS1;D1-tdTomato mice. Recordings were performed using a CsCl-based internal solution containing QX-314 and TEA, in ACSF containing picrotoxin and D-APV. After a 10-min baseline period, mGluR-dependent LTD was induced by bath application of DHPG for 5 min. NASPM was subsequently applied from 35 to 50 min. Period 1 corresponds to baseline (0–10 min), period 2 to the final 5 min before NASPM application (30–35 min), used to quantify DHPG-induced LTD, and period 3 to the final 5 min of NASPM application (45–50 min). (B) Representative paired-pulse AMPAR-mediated eEPSCs recorded from D1R+ and D1R− MSNs in WT;D1-tdTomato (black) and APP/PS1;D1-tdTomato (red) mice during baseline (1), after DHPG-induced LTD (2), and during NASPM application (3). Scale bars: 50 pA, 40 ms. (C) Time course of normalized eEPSC amplitude in D1R+ and D1R− MSNs. DHPG-induced LTD was impaired in APP/PS1 D1R+ MSNs, whereas D1R− MSNs showed comparable synaptic depression between genotypes. Subsequent NASPM application produced an additional reduction in residual eEPSC amplitude selectively in APP/PS1 D1R+ MSNs. Horizontal bars indicate the periods of DHPG and NASPM application. Symbols and shaded regions represent mean ± SD. (D) Quantification of normalized eEPSC amplitude during baseline (1; 0–10 min), after DHPG-induced LTD (2; 30–35 min), and during the final 5 min of NASPM application (3; 45–50 min). The mixed-effects model showed significant effects of experimental stage and group, as well as a significant stage × group interaction (stage, F(1.841,38.67) = 137.8, p < 0.001; experimental group, F(3,21) = 4.459, p = 0.014; stage × experimental group interaction, F(5.524,38.67) = 5.484, p < 0.001). Tukey's multiple-comparisons test showed significant LTD relative to baseline in WT D1R+ (p < 0.001), WT D1R− (p < 0.001), and APP/PS1 D1R− MSNs (p < 0.001), whereas no significant depression was detected in APP/PS1 D1R+ MSNs after DHPG application ( p = 0.293). During the LTD period, normalized eEPSC amplitude was higher in APP/PS1 D1R+ MSNs than in WT D1R+ MSNs ( p = 0.031) and APP/PS1 D1R− MSNs (p = 0.014), whereas WT and APP/PS1 D1R− MSNs did not differ ( p = 0.995). NASPM significantly reduced residual eEPSC amplitude in APP/PS1 D1R+ MSNs relative to the LTD period ( p = 0.020) but produced no additional significant inhibition in WT D1R+ ( p = 0.939), WT D1R− ( p = 0.788), or APP/PS1 D1R− MSNs ( p = 0.921). No significant differences among groups remained during the final NASPM period. (E) Paired-pulse ratio expressed as the ratio between post-LTD and pre-LTD values. No significant differences were detected among groups (Kruskal–Wallis test: H(3) = 2.02, p = 0.570). Each point represents one neuron recorded from a separate acute brain slice, with only one neuron recorded per slice. For panels C–D, the numbers of neurons/mice were: WT D1R+, n = 7/4; WT D1R−, n = 5/4; APP/PS1 D1R+, n = 7/5; and APP/PS1 D1R−, n = 6/5. For panel E, the numbers of neurons/mice were: WT D1R+, n = 6/4; WT D1R−, n = 5/4; APP/PS1 D1R+, n = 7/5; and APP/PS1 D1R−, n = 6/5. Bars and error bars represent mean ± SD, and individual data points are shown. * p < 0.05. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Article Snippet: Recording pipettes (4–5 MΩ) were pulled from borosilicate glass capillaries (WPI) using a horizontal puller (P-1000, Sutter Instruments).

Techniques: Transmission Assay, Transcranial Magnetic Stimulation, Produced, Inhibition, Slice Preparation