Synergistic Activation of Dopamine D1 and TrkB Receptors Mediate Gain Control of Synaptic Plasticity in the Basolateral Amygdala

Chenchen Li,Joanna Dabrowska,Donald G Rainnie,Rimi Hazra,Masabumi Minami

doi:10.1371/journal.pone.0026065

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.

Highlights

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]
We reasoned that theta frequency modulation of synaptic transmission onto BLA principal neurons may play a significant role in fear memory formation
To the best of our knowledge, this study represents the first of its kind to show that a) endogenous dopamine release and subsequent D1 receptor activation is prerequisite for long-term potentiation of glutamatergic input onto BLA principal neurons from cortical afferents, b) that endogenous release of dopamine, zinc, and brain-derived neurotrophic factor (BDNF) results in a synergistic activation of D1 and tyrosine kinase receptor B (TrkB) receptors, which together function to lower the threshold for LTP induction, and that c) convergent activation of the MEK-ERK signaling cascade may play a critical role in lowering the threshold for LTP induction

Summary

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]. The D1 family of dopamine receptors bi-directionally modulates fear memory formation, with activation facilitating and inhibition attenuating recall [4,5]. Consistent with this observation, activation of the amygdala in response to fearful faces is dependent on D1 but not D2 receptor occupancy [6]. 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]

Methods

Results

Conclusion