Original Article

Neuropsychopharmacology (2008) 33, 2416–2426; doi:10.1038/sj.npp.1301642; published online 28 November 2007

Disruption of AMPA Receptor Endocytosis Impairs the Extinction, but not Acquisition of Learned Fear

Gemma L Dalton1,2, Yu Tian Wang3,4, Stan B Floresco1,4 and Anthony G Phillips2,4

  1. 1Department of Psychology, University of British Columbia, Vancouver, BC, Canada
  2. 2Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
  3. 3Department of Medicine, University of British Columbia, Vancouver, BC, Canada
  4. 4Brain Research Centre, Vancouver Coastal Health Research Institute and University of British Columbia, Vancouver, BC, Canada

Correspondence: Dr SB Floresco, Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC, Canada V6T 1Z4. Tel: +1 604 827 5313; Fax: +1 604 822 6923; E-mail: floresco@psych.ubc.ca; Dr AG Phillips, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 2A1. Tel: +1 604 822 4624; Fax: +1 604 822 7756; E-mail: aphillips@psych.ubc

Received 23 July 2007; Accepted 27 October 2007; Published online 28 November 2007.

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Abstract

Synaptic plasticity in the form of long-term potentiation (LTP) plays a critical role in the formation of a Pavlovian fear association. However, the role that synaptic plasticity plays in the suppression of a learned fear response remains to be clarified. Here, we assessed the role that long-term depression (LTD) plays in the acquisition, expression, and extinction of a conditioned fear response. We report that blockade of LTD with a GluR2-derived peptide (Tat-GluR23Y; 1.5μmol/kg, i.v.) that blocks regulated α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor endocytosis during an initial extinction training session disrupted both the expression and recall of extinction learning. A similar impairment of extinction during training, but not recall, was observed when NMDA receptor-dependent LTD was inhibited through the selective blockade of NMDA NR2B receptors with Ro 25-6981. In contrast, blockade of LTD with Tat-GluR23Y during fear conditioning or during a fear recall test did not effect the expression or recall of either contextual or cue-induced conditioned fear. Similarly, administration of Tat-GluR23Y prior to an extinction recall test did not affect spontaneous recovery or rate of re-extinction in previously extinguished rats. These data demonstrate that AMPA receptor endocytosis does not mediate acquisition or expression of conditioned fear, but may play a role in the extinction of fear memories. Furthermore, these findings suggest that LTD may be a molecular mechanism that facilitates the selective modification of a learned association while leaving intact the ability to form a new memory.

Keywords:

long-term depression, amygdala, NMDA, Pavlovian conditioning, rat

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