Presynaptic 5-HT2A receptors are required for the induction of t-LTD at thalamocortical synapses. (A) A post-before-pre pairing protocol, consisting in five spikes at 10 Hz paired 15 times every 10 s with MK-801 (1 mM) delivered into the recording pipette induces t-LTD at thalamocortical synapses in acute PFC slices from WT mice only when DOI (1 μM) was applied in the bath (containing normal ACSF with 1 mM MgCl2 and 2 mM CaCl2) during the pairing protocol. The graph shows average AMPA currents recorded for 45 min after pairing performed in absence (n = 4, P > 0.05; gray dots) or presence of DOI in slices from WT mice (n = 7, P < 0.001; black dots) and of PFC-infected WT mice (postsynaptic infection, Post I., n = 4, P < 0.01; green dots). (B) t-LTD induction was absent in PFC slices from 5-HT2A−/− mice in both the absence (n = 4, P > 0.05; opened gray dots) or presence of DOI (n = 7, P > 0.05; open black dots) as well as in PFC-infected 5-HT2A−/− mice (Post R.) in the presence of DOI (n = 6, P > 0.05; open green dots). (C) t-LTD induction was restored in PFC slices from MD-infected 5-HT2A−/− mice (Pre R.) when DOI was perfused during the pairing protocol (n = 5, P < 0.001; green dots). (D) Quantification of depression at 45–50 min after pairing. **P < 0.01, ***P < 0.001 vs. the corresponding baseline; ##P < 0.01, ###P < 0.001; one-way ANOVA followed by Newman–Keuls test. See also Fig. S6.