Synergistic Activation of Dopamine D1 and TrkB Receptors Mediate Gain Control of Synaptic Plasticity in the Basolateral Amygdala Chenchen Li1,2, Joanna Dabrowska1,2, Rimi Hazra1,2, Donald G. Rainnie1,2* 1 Behavioral Neuroscience and Psychiatric Disorders, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America, 2 Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia, United States of America Abstract Fear memory formation is thought to require dopamine, brain-derived neurotrophic factor (BDNF) and zinc release in the basolateral amygdala (BLA), as well as the induction of long term potentiation (LTP) in BLA principal neurons. However, no study to date has shown any relationship between these processes in the BLA. Here, we have used in vitro whole-cell patch clamp recording from BLA principal neurons to investigate how dopamine, BDNF, and zinc release may interact to modulate the LTP induction in the BLA. LTP was induced by either theta burst stimulation (TBS) protocol or spaced 5 times high frequency stimulation (5xHFS). Significantly, both TBS and 5xHFS induced LTP was fully blocked by the dopamine D1 receptor antagonist, SCH23390. LTP induction was also blocked by the BDNF scavenger, TrkB-FC, the zinc chelator, DETC, as well as by an inhibitor of matrix metalloproteinases (MMPs), gallardin. Conversely, prior application of the dopamine reuptake inhibitor, GBR12783, or the D1 receptor agonist, SKF39393, induced robust and stable LTP in response to a sub- threshold HFS protocol (2xHFS), which does not normally induce LTP. Similarly, prior activation of TrkB receptors with either a TrkB receptor agonist, or BDNF, also reduced the threshold for LTP-induction, an effect that was blocked by the MEK inhibitor, but not by zinc chelation. Intriguingly, the TrkB receptor agonist-induced reduction of LTP threshold was fully blocked by prior application of SCH23390, and the reduction of LTP threshold induced by GBR12783 was blocked by prior application of TrkB-FC. Together, our results suggest a cellular mechanism whereby the threshold for LTP induction in BLA principal neurons is critically dependent on the level of dopamine in the extracellular milieu and the synergistic activation of postsynaptic D1 and TrkB receptors. Moreover, activation of TrkB receptors appears to be dependent on concurrent release of zinc and activation of MMPs. Citation: Li C, Dabrowska J, Hazra R, Rainnie DG (2011) Synergistic Activation of Dopamine D1 and TrkB Receptors Mediate Gain Control of Synaptic Plasticity in the Basolateral Amygdala. PLoS ONE 6(10): e26065. doi:10.1371/journal.pone.0026065 Editor: Masabumi Minami, Hokkaido University, Japan Received May 10, 2011; Accepted September 19, 2011; Published October 14, 2011 Copyright: 2011 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by National Institute of Mental Health grant (MH069852) to D.G.R. and the base center grant to the Yerkes National Primate Research Center #RR-00165, Animal Resource Program at NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: drainni@emory.edu Introduction Evidence from behavioral and electrophysiological studies indicates that the induction of long term potentiation (LTP) in principal neurons of the basolateral amygdala (BLA) may underlie the acquisition and consolidation of fear memories [1,2]. Significantly, fear memory formation is critically dependent on the activation of dopaminergic afferents to the amygdala. Total dopamine depletion prevents fear memory formation, an effect that can be reversed by selective restoration of dopamine release in the pathway from the ventral tegmentum to the BLA [3]. Moreover, the D1 family of dopamine receptors bi-directionally modulates fear memory formation, with activation facilitating and inhibition attenuating recall [4,5]. Consistent with this observa- tion, activation of the amygdala in response to fearful faces is dependent on D1 but not D2 receptor occupancy [6]. We have shown that D1 receptors are found in close association with NMDA receptors in the spines of BLA principal neurons [7], where they function to modulate excitatory synaptic transmission [8]. Hence, D1 receptors appear to be optimally positioned to regulate the induction and expression of LTP in afferent inputs to the BLA. Consistent with this hypothesis, the D1 receptor antagonist, SCH23390, blocks low-frequency stimulation-induced LTP in cortical inputs to the lateral amygdala [9], and D1 receptor activation enhances both the duration and the magnitude of LTP elsewhere in the brain [10]. Similarly, brain-derived neurotrophic factor (BDNF) has been implicated in many forms of synaptic plasticity associated with fear memory formation, including LTP [11,12]. High levels of BDNF and its cognate receptor, tyrosine kinase receptor B (TrkB), are found in the BLA [13,14], and recent studies have shown that TrkB activation in the BLA is necessary for the acquisition and consolidation of fear memories [14,15]. Consistent with these data, a recent study has shown that the non-peptide TrkB receptor agonist, 7, 8-dihydroxyflavone, enhanced both the acquisition of fear and its extinction [16]. Moreover, point mutations of the two main phosphorylation docking sites on the TrkB receptor have been shown to modulate the both acquisition and consolidation of fear learning and amygdala synaptic plasticity [17]. Together these data suggest that BDNF and dopamine may play similar roles in PLoS ONE | www.plosone.org 1 October 2011 | Volume 6 | Issue 10 | e26065