Enduring abolishment of remote but not recent expression of conditioned fear by the blockade of calcium-permeable AMPA receptors before extinction training

D. Zelena, E. Mikics, Diána Balázsfi, János Varga, Barbara Klausz, Eszter Urbán, Eszter Sipos, László Biró, Christina Miskolczi, K. Kovács, Szilamér Ferenczi, J. Haller

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Rationale: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalPsychopharmacology
DOIs
Publication statusAccepted/In press - Mar 28 2016

Fingerprint

AMPA Receptors
Fear
Calcium
Messenger RNA
Prefrontal Cortex
Psychological Extinction
Post-Traumatic Stress Disorders
Amygdala
Anxiety
Learning

Keywords

  • Calcium-permeable AMPA receptor
  • Extinction
  • Fear
  • Glutamate
  • Recovery

ASJC Scopus subject areas

  • Pharmacology

Cite this

Enduring abolishment of remote but not recent expression of conditioned fear by the blockade of calcium-permeable AMPA receptors before extinction training. / Zelena, D.; Mikics, E.; Balázsfi, Diána; Varga, János; Klausz, Barbara; Urbán, Eszter; Sipos, Eszter; Biró, László; Miskolczi, Christina; Kovács, K.; Ferenczi, Szilamér; Haller, J.

In: Psychopharmacology, 28.03.2016, p. 1-12.

Research output: Contribution to journalArticle

Zelena, D. ; Mikics, E. ; Balázsfi, Diána ; Varga, János ; Klausz, Barbara ; Urbán, Eszter ; Sipos, Eszter ; Biró, László ; Miskolczi, Christina ; Kovács, K. ; Ferenczi, Szilamér ; Haller, J. / Enduring abolishment of remote but not recent expression of conditioned fear by the blockade of calcium-permeable AMPA receptors before extinction training. In: Psychopharmacology. 2016 ; pp. 1-12.
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abstract = "Rationale: 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. Methods: 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. Results: 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. Conclusions: 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.",
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AU - Mikics, E.

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AU - Varga, János

AU - Klausz, Barbara

AU - Urbán, Eszter

AU - Sipos, Eszter

AU - Biró, László

AU - Miskolczi, Christina

AU - Kovács, K.

AU - Ferenczi, Szilamér

AU - Haller, J.

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