Acta Pharmacologica Sinica (2011) 32: 1–2 npg © 2011 CPS and SIMM All rights reserved 1671-4083/11 $32.00 www.nature.com/aps

Research Highlight

Erasing fear — key receptor and essential timeframe discovered

Shigenori KAWAHARA

Acta Pharmacologica Sinica (2011) 32: 1–2; doi: 10.1038/aps.2010.215; published online 20 Dec 2010

t is clinically important to suppress eral , an essential region of the current, indicating that reacti- Ior inhibit , which for learning. They suggested that vation followed by extinction attenuates are formed after fearful experiences. In removal of Ca2+-permeable-AMPARs, the potentiated transmission caused by animal models, fear memory is formed the content of which in the is . Electrophysiologi- by repetitive presentation of a tone elevated for a few days after fear condi- cal and pharmacological examinations paired with an electrical foot-shock[1]. It tioning, is responsible for the permanent suggested that this reversal change is well known that an extinction proto- erasure of the fear memory by that pro- of synaptic transmission is due to the col, in which the tone is repeatedly pre- tocol. selective removal of Ca2+-permeable- sented without the foot-shock, gradually First, they demonstrated an enhance- AMPARs, which are enriched 24 h after decreases the pre-acquired fear response ment of Ca2+-permeable-AMPAR medi- conditioning. Consistent with this, to the tone. However, this fear extinc- ated excitatory postsynaptic currents in LTD induction was greatly reduced tion protocol is not sufficient to erase fear-conditioned animals, suggesting in the animals receiving the retrieval– the fear memory; fear responses may an incorporation of Ca2+-permeable- extinction protocol, compared with recover spontaneously or relapse under AMPARs or a change of subunit compo- those receiving extinction alone. This is some conditions. If the fear memory is sition of AMPAR to the Ca2+-permeable because memory retrieval prior to the retrieved or reactivated by a single pre- type. This increase of Ca2+-permeable- extinction removes the Ca2+-permeable- sentation of the tone without the shock AMPARs peaked at 24 h after condition- AMPARs from the synapses, and so fur- 1 h before the extinction session, the fear ing and disappeared by d 7, whereas ther reduction in synaptic transmission responses are permanently removed the total amount of AMPARs remained would not be observed. In addition, by this retrieval–extinction protocol[2]. increased even after 7 d. These results memory reactivation is not effective This suggests that a critical brain state suggest the presence of an important when carried out 7 d after the condition- is caused by the retrieval procedure, in time window, during which AMPARs ing, when the Ca2+-permeable-AMPARs which the fear memory becomes labile transiently change their subunit com- return to the basal level, supporting the and can be destroyed by the subse- position to the Ca2+-permeable type. idea that successful erasure of the fear quent extinction procedure. Clem and Increased Ca2+-permeable-AMPARs at memory requires an abundance of Ca2+- Huganir[3] have found a critical receptor 24 h after fear conditioning was also permeable-AMPARs at the time of the for the permanent erasure of fear memo- supported by an enhancement of long- retrieval-extinction treatment. ries by this retrieval–extinction protocol. term depression (LTD), which is caused Finally, they investigated the molecu- They focused on the Ca2+-permeable by selective removal of Ca2+-permeable- lar mechanisms underlying the elevation type of α-amino-3-hydroxyl-5-methyl- AMPARs that become abundant at that of Ca2+-permeable-AMPAR content after 4-isoxazole-propionate receptor (Ca2+- time. fear conditioning, which is a prerequisite permeable-AMPAR) located in the lat- Next, they examined the effects of for removal of Ca2+-permeable-AMPARs memory retrieval on Ca2+-permeable- by the retrieval–extinction protocol. It Graduate School of Science and Engineering, AMPARs measured after extinction. was reported that phosphorylation of the University of Toyama, 3190 Gofuku, Toyama They found that reactivation of the fear serine 845 (S845) residue of glutamate 930–8555, Japan Correspondence: Prof Shigenori KAWAHARA memory before the extinction session receptor 1 (GluR1) by protein kinase A ([email protected]) significantly decreased AMPA-mediated (PKA) is required for stable expression npg Research Highlight 2

of Ca2+-permeable-AMPARs[4]. Using the transient up-and-down change in level 24 h after fear conditioning and mutant mice with an alanine substitu- the amount of Ca2+-permeable-AMPARs then gradually decline within a few tion mutation of S845 (S845A), they in the lateral amygdala synapses has a days, the treatment will only be effec- showed that phosphorylation of Ca2+- crucial role in permanent erasure of the tive within this time window. Further permeable-AMPARs by PKA is criti- fear memory and that phosphorylation attempts to artificially induce Ca2+- cal for the increase of Ca2+-permeable- of Ca2+-permeable-AMPARs by PKA is permeable-AMPAR accumulation might AMPAR current and the enhancement involved in their up-regulation. Inter- remove the time limit and make the of LTD 24 h after fear conditioning. estingly, S845A mutant mice showed a treatment successful beyond this narrow These results suggest the importance significant post-conditioning synaptic timeframe. of phosphorylation of S845 for the syn- potentiation in the lateral amygdala and aptic incorporation of Ca2+-permeable- learned as successfully as the wildtype AMPARs. In parallel with the deficits mice. These results indicate that phos- in the post-conditioning dynamics of phorylation of S845 and its resulting 1 Herry C, Ferraguti F, Singewald N, Letzkus JJ, Ehrlich Ca2+-permeable-AMPARs, memory Ca2+-permeable-AMPAR dynamics are I, Lüthi A. Neuronal circuits of fear extinction. Eur J Neurosci 2010; 31: 599–612. erasure by the retrieval-extinction pro- specifically related to the memory era- 2 Monfils MH, Cowansage KK, Klann E, LeDoux tocol was impaired in these mutant sure processes triggered by the retrieval– JE. Extinction-reconsolidation boundaries: key to mice. Because phosphorylation of Ca2+- extinction protocol. persistent attenuation of fear memories. Science 2009; 324: 951–5. permeable-AMPARs by PKA is blocked In addition to molecular strategies for 3 Clem RL, Huganir RL. Calcium-permeable AMPA throughout the brain in these mutant treatment of traumatic memories, these receptor dynamics mediate fear memory erasure. mice, there is a possibility that the lack data also provide important informa- Science 2010; 330: 1108–12. 4 He K, Song L, Cummings LW, Goldman J, Huganir of the erasure effect might be due to tion on the right timing of the treatment: RL, Lee H-K. Stabilization of Ca2+-permeable AMPA impairments in other regions outside there is a critical or effective period for receptors at perisynaptic sites by GluR1-S845 the lateral amygdala. Combined with the memory erasure. Because Ca2+- phosphorylation. Proc Natl Acad Sci USA 2009; 106: 20033–8. other data, however, it is suggested that permeable-AMPARs reach a maximum

Acta Pharmacologica Sinica