NMDA Currents and Receptor Protein Are Downregulated in the Amygdala during Maintenance of Fear Memory

Abstract

The amygdala plays a critical role in fear conditioning, a model of emotional learning and cue-induced anxiety. In the lateral amygdala, fear conditioning is associated with an enduring increase in synaptic strength mediated through AMPA receptors and with a reduction in paired-pulse facilitation, reflecting an increased probability of neurotransmitter release. Here we show that NMDA-mediated transmission in the thalamic-to-lateral amygdala pathway is not facilitated after fear conditioning, although probability of transmitter release is enhanced. Rather, the EC 50 for NMDA receptor (NR)-mediated current is shifted threefold to fourfold to the right in fear-conditioned animals, suggesting a postsynaptic alteration in NMDA receptors in the maintenance phase of fear memory. Furthermore, the ability of nonselective and subunit-selective antagonists of NMDA receptors to block NMDA receptor-mediated EPSCs is reduced in lateral amygdala neurons from fear-conditioned animals, suggesting a reduction in NMDA receptors at thalamolateral amygdala synapses. In addition, Western blots show a reduction in phosphorylated-NR1, NR2A, and NR2B subunit protein expression in amygdalas from fearconditioned animals. These data indicate that postsynaptic mechanisms are involved in synaptic plasticity in the thalamoamygdala pathway in fear conditioning and raise the possibility that: (1) downregulation of the NMDA receptor may protect against excitotoxicity of unchecked NMDA receptor recruitment during induction and consolidation of fear memories, (2) reduced NMDA current and protein may allow persistence of the "capacity to reactivate" amygdala pathways in NMDA receptor-dependent fear memories, or (3) a persistent long-term depression of NMDA transmission may occur after fear learning.

Advances in the treatment of anxiety: Targeting glutamate

“…See reviews by Manji et al 17 and Duman and Carlson et al 115,116 This shrinkage appears to disrupt the functionality of the neurons and their signaling, but it may in fact be compensatory or adaptive. 117 In postsynaptic neurons in the CNS, NMDA and AMPA receptors are actively shuttled between the membrane and cytoplasm by a clathrindependent mechanism 118 ; of note, in mature cultures, NR2B undergoes more robust endocytosis than NR2A, consistent with previous studies showing NR2A to be more highly expressed at stable synaptic sites. 119 Thus, one mechanism for terminating excessive glutamatergic neurotransmission and the sustained activation of NMDA receptors is the internalization of these receptors.…”

“…118 Interestingly, NMDA receptors are functionally downregulated at synapses as a result of fear learning. 117 We hypothesize that, during acute stress, internalization of glutamatergic receptors occurs and functions as an adaptive method of reducing the excitotoxic effects of glutamate on postsynaptic neurons, and during more excessive or prolonged stress, the neuron further adaptively reduces the number of available glutamate receptors by reducing dendrite length and spine number to protect itself from glutamate-induced cell death. Although this limits glutamatergic toxic effects on the neuron and may preserve the cell body, it essentially disconnects the neuron from other neurons by reducing the number of synaptic connections, thereby preventing cell death, but possibly precipitating anxiety or depressive disorders.…”

The E3 ligase APC/C–Cdh1 is required for associative fear memory and long-term potentiation in the amygdala of adult mice

“…For example, NR2A levels in the rat amygdala are normally reduced after fear conditioning (Zinebi et al 2003), suggesting that increased NR2A levels could lead to altered fear memory. In addition, increased levels of NR2A in the amygdala are associated with depression (Karolewicz et al 2009).…”

Increasing the GluN2A/GluN2B Ratio in Neurons of the Mouse Basal and Lateral Amygdala Inhibits the Modification of an Existing Fear Memory Trace

“…Notably, strong fear memories that do not undergo retrieval-dependent destabilization are associated with a reduction in GluN2B subunits in the BLA (Wang et al, 2009). It has been speculated that learning-induced changes in NMDAR subunit composition serve as a mechanism for maintaining the integrity of the memory and prevent memory destabilization upon retrieval (Zinebi et al, 2003, Quinlan et al, 2004, Wang et al, 2009; however, this has never been tested experimentally.…”