Prefrontal Infusion of PD098059 Immediately After Fear Extinction Training Blocks Extinction-Associated Prefrontal Synaptic Plasticity and Decreases Prefrontal ERK2 Phosphorylation SANDRINE HUGUES, 1 ALINE CHESSEL, 1 ISABELLE LENA, 1 ROBERT MARSAULT, 2 AND RENE GARCIA 1 * 1 Laboratoire de Neurobiologie et Psychopathologie, Faculte ´ des Sciences, Universite ´ de Nice-Sophia Antipolis, Nice, France 2 Transporteurs en Imagerie et Radiotherapie en Oncologie, Faculte ´ de Me ´decine, Universite ´ de Nice-Sophia Antipolis, Nice, France KEY WORDS fear extinction and return; prefrontal LTP; protein kinases; rats ABSTRACT A previous study has demonstrated that disruption of fear extinction- induced long-term potentiation (LTP) in the medial prefrontal cortex (mPFC) is associ- ated with the return of fear responding. Given that immediate posttraining infusion of PD098059, an inhibitor of extracellular signal-regulated kinase (ERK) mitogen-acti- vated protein kinase (MAPK) cascade, into the mPFC also promotes recovery of fear, we investigated whether impairment of mPFC ERK/MAPK cascade also interferes with de- velopment of extinction-related LTP in the mPFC in rats. In Experiment 1, extinction training consisting of repetitive presentations of a tone previously associated with eye- lid-shock application induced LTP-like changes at hippocampal inputs to the mPFC that were evident for 2 h following fear extinction. Infusion of PD098059 into the mPFC immediately after extinction training abolished training-related prefrontal LTP and impaired retention of extinction memory tested on the following day. In Experiment 2, immunoblotting assays revealed that posttraining infusion of PD098059 into the mPFC produced a significant reduction of mPFC ERK2. These data, along with previ- ous findings, suggest that low levels of ERK2 phosphorylation in the mPFC may inter- fere with mechanisms of retention of extinction training. The involvement of mPFC LTP in fear extinction is discussed. Synapse 60:280–287, 2006. V V C 2006 Wiley-Liss, Inc. INTRODUCTION Synapses can undergo long-lasting changes in strength during a memory task, including extinction training. Studies using, for example, field potential recordings have shown that extinction of conditioned fear is asso- ciated with long-term potentiation (LTP)-like changes in the medial prefrontal cortex (mPFC) (Herry and Garcia, 2002). In the same studies, we have found that mice which display LTP-like changes in the mPFC fol- lowing extinction training exhibit long-term retention of fear extinction memory, whereas mice that fail to dis- play such changes exhibit recovery of conditioned fear on subsequent tests. Further, blockade of extinction- induced LTP in the mPFC by low-frequency stimula- tion of the mediodorsal thalamus (MD) promotes return of fear (Herry and Garcia, 2002). Collectively, these findings suggest that enhancements of mPFC neuronal activity following extinction training are involved in long-term memory of fear extinction (see also Milad and Quirk, 2002). Despite this evidence, one cannot conclude that the mPFC is essential for extinction memory. Indeed, elec- trophysiological changes observed in this area may correlate, or be reflective of, behavioral changes with- Contract grant sponsor: De ´le ´gation Ge ´ne ´rale pour l’Armement. *Correspondence to: Rene ´ Garcia, Ph.D.; Laboratoire de Neurobiologie et Psychopathologie, Universite ´ de Nice-Sophia Antipolis, Parc Valrose, 06108 Nice, France. E-mail: rgarcia@unice.fr Received 14 October 2005; Accepted 28 March 2006 DOI 10.1002/syn.20291 Published online in Wiley InterScience (www.interscience.wiley.com). V V C 2006 WILEY-LISS, INC. SYNAPSE 60:280–287 (2006)