PMID- 25510511
OWN - NLM
STAT- MEDLINE
DCOM- 20160324
LR  - 20240214
IS  - 1476-5578 (Electronic)
IS  - 1359-4184 (Print)
IS  - 1359-4184 (Linking)
VI  - 20
IP  - 7
DP  - 2015 Jul
TI  - Durable fear memories require PSD-95.
PG  - 901-12
LID - 10.1038/mp.2014.161 [doi]
AB  - 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.
FAU - Fitzgerald, P J
AU  - Fitzgerald PJ
AD  - Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol 
      Abuse and Alcoholism, NIH, Bethesda, MD, USA.
FAU - Pinard, C R
AU  - Pinard CR
AD  - Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol 
      Abuse and Alcoholism, NIH, Bethesda, MD, USA.
FAU - Camp, M C
AU  - Camp MC
AD  - Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol 
      Abuse and Alcoholism, NIH, Bethesda, MD, USA.
FAU - Feyder, M
AU  - Feyder M
AD  - Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol 
      Abuse and Alcoholism, NIH, Bethesda, MD, USA.
FAU - Sah, A
AU  - Sah A
AD  - Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, 
      University of Innsbruck, Innsbruck, Austria.
FAU - Bergstrom, H C
AU  - Bergstrom HC
AUID- ORCID: 0000000336771619
AD  - Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol 
      Abuse and Alcoholism, NIH, Bethesda, MD, USA.
FAU - Graybeal, C
AU  - Graybeal C
AD  - Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol 
      Abuse and Alcoholism, NIH, Bethesda, MD, USA.
FAU - Liu, Y
AU  - Liu Y
AUID- ORCID: 0000000314435825
AD  - Picower Institute for Learning and Memory, Department of Brain and Cognitive 
      Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
FAU - Schluter, O M
AU  - Schluter OM
AD  - European Neuroscience Institute, Gottingen, Germany.
FAU - Grant, S G
AU  - Grant SG
AD  - Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The 
      University of Edinburgh, Edinburgh, UK.
FAU - Singewald, N
AU  - Singewald N
AD  - Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, 
      University of Innsbruck, Innsbruck, Austria.
FAU - Xu, W
AU  - Xu W
AD  - Picower Institute for Learning and Memory, Department of Brain and Cognitive 
      Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
FAU - Holmes, A
AU  - Holmes A
AD  - Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol 
      Abuse and Alcoholism, NIH, Bethesda, MD, USA.
LA  - eng
GR  - Z99 AA999999/ImNIH/Intramural NIH HHS/United States
GR  - K99 MH080310/MH/NIMH NIH HHS/United States
GR  - P 22931/FWF_/Austrian Science Fund FWF/Austria
GR  - NIH MH080310/MH/NIMH NIH HHS/United States
GR  - R00 MH080310/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20141216
PL  - England
TA  - Mol Psychiatry
JT  - Molecular psychiatry
JID - 9607835
RN  - 0 (Disks Large Homolog 4 Protein)
RN  - 0 (Dlg4 protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - EC 2.7.4.8 (Guanylate Kinases)
SB  - IM
EIN - Mol Psychiatry. 2015 Jul;20(7):913. PMID: 25824301
MH  - Action Potentials/physiology
MH  - Animals
MH  - Cerebral Cortex/cytology/*physiology
MH  - Conditioning, Classical/physiology
MH  - Cues
MH  - Dendritic Spines/metabolism
MH  - Disks Large Homolog 4 Protein
MH  - Electrodes, Implanted
MH  - Electroshock
MH  - Extinction, Psychological/physiology
MH  - Fear/*physiology
MH  - Female
MH  - Freezing Reaction, Cataleptic/physiology
MH  - Gamma Rhythm/physiology
MH  - Gene Knockdown Techniques
MH  - Guanylate Kinases/genetics/*metabolism
MH  - Male
MH  - Membrane Proteins/genetics/*metabolism
MH  - Memory/*physiology
MH  - Mice, Mutant Strains
MH  - Olfactory Perception/physiology
MH  - Pyramidal Cells/cytology/physiology
MH  - Theta Rhythm/physiology
PMC - PMC4469631
MID - NIHMS635900
COIS- Conflicts of interest and financial disclosures The authors have no conflicts or 
      competing interests to declare.
EDAT- 2014/12/17 06:00
MHDA- 2016/03/25 06:00
PMCR- 2016/01/01
CRDT- 2014/12/17 06:00
PHST- 2014/02/04 00:00 [received]
PHST- 2014/07/28 00:00 [revised]
PHST- 2014/10/15 00:00 [accepted]
PHST- 2014/12/17 06:00 [entrez]
PHST- 2014/12/17 06:00 [pubmed]
PHST- 2016/03/25 06:00 [medline]
PHST- 2016/01/01 00:00 [pmc-release]
AID - mp2014161 [pii]
AID - 10.1038/mp.2014.161 [doi]
PST - ppublish
SO  - Mol Psychiatry. 2015 Jul;20(7):901-12. doi: 10.1038/mp.2014.161. Epub 2014 Dec 
      16.