title: Durable fear memories require PSD-95.
abstract: Traumatic fear memories are highly durable but also dynamic, undergoing repeated reactivation and rehearsal over time. Although overly persistent fear memories underlie anxiety disorders, such as posttraumatic stress disorder, the key neural and molecular mechanisms underlying fear memory durability remain unclear. Postsynaptic density 95 (PSD-95) is a synaptic protein regulating glutamate receptor anchoring, synaptic stability and certain types of memory. Using a loss-of-function mutant mouse lacking the guanylate kinase domain of PSD-95 (PSD-95(GK)), we analyzed the contribution of PSD-95 to fear memory formation and retrieval, and sought to identify the neural basis of PSD-95-mediated memory maintenance using ex vivo immediate-early gene mapping, in vivo neuronal recordings and viral-mediated knockdown (KD) approaches. We show that PSD-95 is dispensable for the formation and expression of recent fear memories, but essential for the formation of precise and flexible fear memories and for the maintenance of memories at remote time points. The failure of PSD-95(GK) mice to retrieve remote cued fear memory was associated with hypoactivation of the infralimbic (IL) cortex (but not the anterior cingulate cortex (ACC) or prelimbic cortex), reduced IL single-unit firing and bursting, and attenuated IL gamma and theta oscillations. Adeno-associated virus-mediated PSD-95 KD in the IL, but not the ACC, was sufficient to impair recent fear extinction and remote fear memory, and remodel IL dendritic spines. Collectively, these data identify PSD-95 in the IL as a critical mechanism supporting the durability of fear memories over time. These preclinical findings have implications for developing novel approaches to treating trauma-based anxiety disorders that target the weakening of overly persistent fear memories.
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Fitzgerald
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Pinard
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Camp
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Feyder
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, University of Innsbruck, Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Sah
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
authors.forename: H C
authors.identifier: 0000000336771619
authors.initials: HC
authors.lastname: Bergstrom
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Graybeal
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Y
authors.identifier: 0000000314435825
authors.initials: Y
authors.lastname: Liu
authors.affiliation: European Neuroscience Institute, Gottingen, Germany.
authors.forename: O M
authors.initials: OM
authors.lastname: Schlüter
authors.affiliation: Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The University of Edinburgh, Edinburgh, UK.
authors.forename: S G
authors.initials: SG
authors.lastname: Grant
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, University of Innsbruck, Innsbruck, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Singewald
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Xu
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Holmes
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D003214:Conditioning, Classical / Q000502:physiology; D003463:Cues; D049229:Dendritic Spines / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004567:Electrodes, Implanted; D004597:Electroshock; D005108:Extinction, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology*; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D065818:Gamma Rhythm / Q000502:physiology; D055785:Gene Knockdown Techniques; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008568:Memory / Q000502:physiology*; D008817:Mice, Mutant Strains; D055696:Olfactory Perception / Q000502:physiology; D017966:Pyramidal Cells / Q000166:cytology / Q000502:physiology; D013826:Theta Rhythm / Q000502:physiology
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D051528:Guanylate Kinases