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.

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-GluR2_3Y; 1.5 mol/kg, i.v.) that blocks regulated -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-GluR2_3Y 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-GluR2_3Y 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.