Abstract
N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) in the lateral nucleus of the amygdala (LA) is a form of synaptic plasticity thought to be a cellular substrate for the extinction of fear memory. The LA receives converging inputs from the sensory thalamus and neocortex that are weakened following fear extinction. Combining field and patch-clamp electrophysiological recordings in mice, we show that paired-pulse low-frequency stimulation can induce a robust LTD at thalamic and cortical inputs to LA, and we identify different underlying molecular components at these pathways. We show that while LTD depends on NMDARs and activation of the protein phosphatases PP2B and PP1 at both pathways, it requires NR2B-containing NMDARs at the thalamic pathway, but NR2C/D-containing NMDARs at the cortical pathway. LTD appears to be induced post-synaptically at the thalamic input but presynaptically at the cortical input, since post-synaptic calcium chelation and NMDAR blockade prevent thalamic but not cortical LTD. These results highlight distinct molecular features of LTD in LA that may be relevant for traumatic memory and its erasure, and for pathologies such as post-traumatic stress disorder (PTSD).
Highlights
Synaptic plasticity, a property of neuronal connections characterized by a change in synaptic strength following neuron activation, is essential for memory formation and for forgetting
N-methyl-D-aspartate receptor (NMDAR)-DEPENDENT long-term depression (LTD) IN lateral amygdala (LA) DEPENDS ON PROTEIN PHOSPHATASES In the hippocampus, the most common form of LTD requires post-synaptic rise in calcium that depends on NMDARs, and is associated with activation of a PP2B/PP1 signaling cascade (Collingridge et al, 2010)
LTD was fully blocked by the NMDAR antagonist D-APV (50 μM) at both, the thalamic and cortical pathway, demonstrating that LA–LTD depends on NMDARs at both pathways
Summary
A property of neuronal connections characterized by a change in synaptic strength following neuron activation, is essential for memory formation and for forgetting. Long-term depression (LTD), a form of synaptic weakening, requires a moderate rise of intracellular calcium concentration that activates protein phosphatases including PP2B (calcineurin) and subsequently PP1 (Mulkey et al, 1993, 1994; Jouvenceau et al, 2003, 2006; Pi and Lisman, 2008). The mechanisms of LTD at the cortical pathway remain unknown, but are postulated to be different from those at the thalamic pathway (Doyere et al, 2003; Humeau et al, 2003) We investigated these mechanisms in adult mouse LA and examined whether they involve the phosphatases PP2B and PP1, and which NMDAR subunits they recruit. We show that LTD is induced postsynaptically at the thalamic pathway, but not at the cortical pathway
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