Dopamine and BDNF Modulate LTP in the BLA Figure 1. Stimulus dependent induction of LTP in BLA principal neurons. A) A schematic illustrating the position of the stimulation (Scortical and Sthalamic) and recording (R) electrodes. EC, external capsule. B) Stimulation of the EC elicits long term synaptic plasticity in BLA afferents following TBS (n = 6, blue diamonds) and 56100 Hz (n = 5, red squares), but not 26100 Hz (n = 8, green triangles). C) Raw data show the effects of different stimulation protocols on the PPR of EPSCs. EPSC amplitude was measured using paired stimuli pulses separated by 50 ms, before, immediately after, and 10 min and 30 min post stimulation. D) A bar chart showing the group data for the effects of stimulation protocol on PPR. Note the large decrease (P ,0.05) immediately post-stim, indicating the presynaptic component of post-tetanic-potentiation. * P,0.05. Error bars indicate S.E.M. doi:10.1371/journal.pone.0026065.g001 These results suggested that the LTP induced by TBS or 5xHFS share common receptor-effector signaling cascades. To assess whether D1 receptor -mediated LTP in the BLA was dependent on activation of the adenylate cyclase (AC) – cAMP - protein kinase A (PKA) signaling cascade, we next tested the effect of inclusion in the patch pipette of a membrane-impermeable AC inhibitor, 29, 59-dideoxy-39-ATP (0.5 mM), on 5xHFS-induced LTP. Intracellular application of 29, 59-dideoxy-39-ATP signifi- cantly attenuated 5xHFS-induced LTP in BLA neurons (Control: 153611% of baseline, n = 5; 29, 59-dideoxy-39-ATP: 110610% of baseline, n = 6; P,0.001). Similarly, intracellular application of the PKA inhibitor, KT5720 (100 nM), blocked not only the TBS- induced LTP (112610% of baseline, n = 5, 4 animals, Figure 2E), but also the 5xHFS-induced LTP (10767% of baseline, n = 5, 4 animals, Figure 2F). However, application of KT5720 caused no enduring change in input resistance at any time point measured (F (15, 98) = 0.26, P = 0.9761, Two-way ANOVA). Hence, the D1 receptor-dependent induction of LTP by either TBS or 5xHFS in BLA principal neurons was also dependent on activation of the AC – cAMP - PKA signaling cascade. Having determined that LTP induction in BLA principal neurons was dependent on local dopamine release and subsequent activation of the D1 receptor - cAMP- PKA signaling cascade, we next examined whether the induction of LTP could be modified following bath application of the dopamine-specific monoamine transport inhibitor, GBR12783 (10 mM). Blockade of dopamine PLoS ONE | www.plosone.org 3 October 2011 | Volume 6 | Issue 10 | e26065