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

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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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Acknowledgments

The authors are grateful to Carmen Sandi for her help in the preparation of this manuscript.

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    Authors and Affiliations

    1. Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083, Budapest, Szigony 43, Hungary

      Dóra Zelena, Éva Mikics, Diána Balázsfi, János Varga, Barbara Klausz, Eszter Urbán, Eszter Sipos, László Biró, Christina Miskolczi, Krisztina Kovács, Szilamér Ferenczi & József Haller

    2. János Szentágothai School of Neurosciences, Semmelweis University, Budapest, Hungary

      Diána Balázsfi & László Biró

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    1. Dóra Zelena
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    Correspondence to Dóra Zelena.

    Ethics declarations

    Experiments were carried out in accordance with the European Communities Council Directive recommendations for the care and use of laboratory animals (2010/63/EU) and were reviewed and approved by the Animal Welfare Committee of the Institute of Experimental Medicine.

    Funding

    This study was supported by OTKA grant no. 101645.

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    The authors declare that they have no conflict of interest.

    Additional information

    Dóra Zelena and Éva Mikics contributed equally to this work.

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    Zelena, D., Mikics, É., Balázsfi, D. et al. Enduring abolishment of remote but not recent expression of conditioned fear by the blockade of calcium-permeable AMPA receptors before extinction training. Psychopharmacology 233, 2065–2076 (2016). https://doi.org/10.1007/s00213-016-4255-4

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