title: Fear extinction induces mGluR5-mediated synaptic and intrinsic plasticity in infralimbic neurons.
abstract: Studies suggest that plasticity in the infralimbic prefrontal cortex (IL) in rodents and its homolog in humans is necessary for inhibition of fear during the recall of fear extinction. The recall of extinction is impaired by locally blocking metabotropic glutamate receptor type 5 (mGluR5) activation in IL during extinction training. This finding suggests that mGluR5 stimulation may lead to IL plasticity needed for fear extinction. To test this hypothesis, we recorded AMPA and NMDA currents, AMPA receptor (AMPAR) rectification, and intrinsic excitability in IL pyramidal neurons in slices from trained rats using whole-cell patch-clamp recording. We observed that fear extinction increases the AMPA/NMDA ratio, consistent with insertion of AMPARs into IL synapses. In addition, extinction training increased inward rectification, suggesting that extinction induces the insertion of calcium-permeable (GluA2-lacking) AMPARs into IL synapses. Consistent with this, selectively blocking calcium-permeable AMPARs with Naspm reduced the AMPA EPSCs in IL neurons to a larger degree after extinction. Extinction-induced changes in AMPA/NMDA ratio, rectification, and intrinsic excitability were blocked with an mGluR5 antagonist. These findings suggest that mGluR5 activation leads to consolidation of fear extinction by regulating the intrinsic excitability of IL neurons and modifying the composition of AMPARs in IL synapses. Therefore, impaired mGluR5 activity in IL synapses could be one factor that causes inappropriate modulation of fear expression leading to anxiety disorders.
authors.affiliation: Department of Pharmacology and Physiology, Ponce School of Medicine, Ponce, Puerto Rico 00732, USA.
authors.forename: Marian T
authors.initials: MT
authors.lastname: Sepulveda-Orengo
authors.forename: Ana V
authors.initials: AV
authors.lastname: Lopez
authors.forename: Omar
authors.initials: O
authors.lastname: Soler-Cedeño
authors.forename: James T
authors.initials: JT
authors.lastname: Porter
mesh_terms: D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear; D008032:Limbic System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate