title: Inhibition of spontaneous recovery of fear by mGluR5 after prolonged extinction training.
abstract: Fear behavior is vital for survival and involves learning contingent associations of non-threatening cues with aversive stimuli. In contrast, excessive levels of fear can be maladaptive and lead to anxiety disorders. Generally, extensive sessions of extinction training correlates with reduced spontaneous recovery. The molecular mechanisms underlying the long-term inhibition of fear recovery following repeated extinction training are not fully understood. Here we show that in rats, prolonged extinction training causes greater reduction in both fear-potentiated startle and spontaneous recovery. This effect was specifically blocked by metabotropic glutamate receptor 5 (mGluR5), but not by mGluR1 antagonists and by a protein synthesis inhibitor. Similar inhibition of memory recovery following prolonged extinction training was also observed in mice. In agreement with the instrumental role of mGluR5 in the prolonged inhibition of fear recovery, we found that FMR1-/- mice which exhibit enhanced mGluR5-mediated signaling exhibit lower spontaneous recovery of fear after extinction training than wild-type littermates. At the molecular level, we discovered that prolonged extinction training reversed the fear conditioning-induced increase in surface expression of GluR1, AMPA/NMDA ratio, postsynaptic density-95 (PSD-95) and synapse-associated protein-97 (SAP97). Accordingly, delivery of Tat-GluR2(3Y), a synthetic peptide that blocks AMPA receptor endocytosis, inhibited prolonged extinction training-induced inhibition of fear recovery. Together, our results demonstrate that prolonged extinction training results in the mGluR5-dependent long-term inhibition of fear recovery. This effect may involve the degradation of original memory and may explain the beneficial effects of prolonged exposure therapy for the treatment of phobias.
authors.affiliation: Institute of Basic Medical Sciences and Department of Pharmacology, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Sheng-Chun
authors.initials: SC
authors.lastname: Mao
authors.forename: Chih-Hua
authors.initials: CH
authors.lastname: Chang
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Wu
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: Orejarena
authors.forename: Maria Juliana
authors.initials: MJ
authors.lastname: Orejanera
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Manzoni
authors.forename: Po-Wu
authors.initials: PW
authors.lastname: Gean
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological; D003463:Cues; D004705:Endocytosis; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology / Q000523:psychology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013997:Time Factors
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat
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