title: Enduring abolishment of remote but not recent expression of conditioned fear by the blockade of calcium-permeable AMPA receptors before extinction training.
abstract: Calcium-permeable (GluA2 subunit-free) AMPA receptors (CP-AMPAR) play prominent roles in fear extinction; however, no blockers of these receptors were studied in tests relevant to extinction learning so far.
  
  
  
  The CP-AMPAR antagonist IEM-1460 was administered once before extinction trainings, which were started either 1 or 28 days after fear conditioning (FC). We used a mild extinction protocol that durably decreased but did not abolish conditioned fear. The messenger RNA (mRNA) expression of GluA1 and GluA2 subunits were investigated at both time points in the ventromedial prefrontal cortex (vmPFC) and amygdala.
  
  
  
  IEM-1460 transiently facilitated extinction 1 day after conditioning, but learned fear spontaneously recovered 4 weeks later. When the extinction protocol was applied 28 days after training, IEM-1460 enhanced extinction memory, moreover abolished conditioned fear for at least a month. The expression of GluA1 and GluA2 mRNAs was increased at both time points in the vmPFC. In the basolateral and central amygdala, the GluA1/GluA2 mRNA ratio increased, suggesting a shift towards the preponderance of GluA1 over GluA2 expression.
  
  
  
  AMPAR blockade lastingly enhanced the extinction of remote but not recent fear memories. Time-dependent changes in AMPA receptor subunit mRNA expression may explain the differential effects of CP-AMPAR blockade on recent and remote conditioned fear, further supporting the notion that the mechanisms maintaining learned fear change over time. Our findings suggest clinical implications for CP-AMPAR blockers, particularly for acquired anxieties (e.g., post-traumatic stress disorder) which have a slow onset and are durable.
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary. zelena.dora@koki.mta.hu.
authors.forename: Dóra
authors.initials: D
authors.lastname: Zelena
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Mikics
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary.|János Szentágothai School of Neurosciences, Semmelweis University, Budapest, Hungary.
authors.forename: Diána
authors.initials: D
authors.lastname: Balázsfi
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Varga
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klausz
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Urbán
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Sipos
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary.|János Szentágothai School of Neurosciences, Semmelweis University, Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Biró
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary.
authors.forename: Christina
authors.initials: C
authors.lastname: Miskolczi
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Kovács
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary.
authors.forename: Szilamér
authors.initials: S
authors.lastname: Ferenczi
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Haller
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000523:psychology*; D006728:Hormones / Q000097:blood; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000218:Adamantane; D002118:Calcium; D006728:Hormones; D012333:RNA, Messenger; D018091:Receptors, AMPA; C110702:IEM 1460; C104722:glutamate receptor ionotropic, AMPA 2
keywords: Calcium-permeable AMPA receptor; Extinction; Fear; Glutamate; Recovery