title: Regulation of fear extinction versus other affective behaviors by discrete cortical scaffolding complexes associated with NR2B and PKA signaling.
abstract: In patients suffering from post-traumatic stress disorder (PTSD), fear evoked by trauma-related memories lasts long past the traumatic event and it is often complicated by general anxiety and depressed mood. This poses a treatment challenge, as drugs beneficial for some symptoms might exacerbate others. For example, in preclinical studies, antagonists of the NR2B subunit of N-methyl-d-aspartate receptors and activators of cAMP-dependent protein kinase (PKA) act as potent antidepressants and anxiolytics, but they block fear extinction. Using mice, we attempted to overcome this problem by interfering with individual NR2B and PKA signaling complexes organized by scaffolding proteins. We infused cell-permeable Tat peptides that displaced either NR2B from receptor for activated C kinase 1 (RACK1), or PKA from A-kinase anchor proteins (AKAPs) or microtubule-associated proteins (MAPs). The infusions were targeted to the retrosplenial cortex, an area involved in both fear extinction of remotely acquired memories and in mood regulation. Tat-RACK1 and Tat-AKAP enhanced fear extinction, all peptides reduced anxiety and none affected baseline depression-like behavior. However, disruption of PKA complexes distinctively interfered with the rapid antidepressant actions of the N-methyl-D-aspartate receptors antagonist MK-801 in that Tat-MAP2 blocked, whereas Tat-AKAP completely inverted the effect of MK-801 from antidepressant to depressant. These effects were unrelated to the MK-801-induced changes of brain-derived neurotrophic factor messenger RNA levels. Together, the findings suggest that NR2B-RACK1 complexes specifically contribute to fear extinction, and may provide a target for the treatment of PTSD. AKAP-PKA, on the other hand, appears to modulate fear extinction and antidepressant responses in opposite directions.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Corcoran
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Leaderbrand
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: V
authors.initials: V
authors.lastname: Jovasevic
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Guedea
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: F
authors.initials: F
authors.lastname: Kassam
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Radulovic
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001526:Behavioral Symptoms / Q000188:drug therapy / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D000075370:Receptors for Activated C Kinase; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; D000928:Antidepressive Agents; C485096:NR2B protein (1292-1308); D009479:Neuropeptides; D010446:Peptide Fragments; C090294:RACK1 protein, mouse; D000075370:Receptors for Activated C Kinase; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D017868:Cyclic AMP-Dependent Protein Kinases