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The Journal of Neuroscience, November 12, 2003, 23(32):10283-10291

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Behavioral/Systems/Cognitive
NMDA Currents and Receptor Protein Are Downregulated in the Amygdala during Maintenance of Fear Memory

Fatiha Zinebi,¹ Jiangang Xie,¹ Jie Liu,¹ Rex T. Russell,² Joel P. Gallagher,¹ Margaret G. McKernan,³ and Patricia Shinnick-Gallagher¹

¹University of Texas Medical Branch, Department of Pharmacology and Toxicology, Galveston, Texas 77555-1031, ²Department of Anesthesiology, Johns Hopkins University, Baltimore, Maryland 21205, and ³Department of Radiology, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157-1088

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 EC₅₀ 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 fear-conditioned 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.

Key words: amygdala; synaptic plasticity; fear conditioning; fear-potentiated startle; memory; learning; NR subunits; ifenprodil; paired-pulse facilitation

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Received June 4, 2003; revised September 17, 2003; accepted September 19, 2003.

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