Elsevier

Biological Psychiatry

Volume 86, Issue 9, 1 November 2019, Pages 682-692
Biological Psychiatry

Archival Report
Diminished Fear Extinction in Adolescents Is Associated With an Altered Somatostatin Interneuron–Mediated Inhibition in the Infralimbic Cortex

https://doi.org/10.1016/j.biopsych.2019.04.035Get rights and content

Abstract

Background

Rodents and humans show an attenuation of fear extinction during adolescence, which coincides with the onset of several psychiatric disorders. Although the ethological relevance and the underlying mechanism are largely unknown, the suppression of fear extinction during adolescence is associated with a diminished plasticity in the glutamatergic neurons of the infralimbic medial prefrontal cortex, a brain region critical for fear extinction. Given the putative effect of synaptic inhibition on glutamatergic neuron activity, we studied whether gamma-aminobutyric acidergic neurons in the infralimbic medial prefrontal cortex are involved in the suppression of fear extinction during adolescence.

Methods

We assessed membrane and synaptic properties in parvalbumin-positive interneurons (PVINs) and somatostatin-positive interneurons (SSTINs) in male preadolescent, adolescent, and adult mice. The effect of fear conditioning and extinction on PVIN-pyramidal neuron and SSTIN-pyramidal neuron synapses in male preadolescent, adolescent, and adult mice was evaluated using an optogenetic approach.

Results

The development of the membrane excitability of PVINs is delayed and reaches maturity only by adulthood, while the SSTIN membrane properties are developed early and remain stable during development from preadolescence to adulthood. Although the synaptic inhibition mediated by PVINs undergoes a protracted development, it does not exhibit a fear behavior–specific plasticity. However, the synaptic inhibition mediated by SSTINs undergoes an adolescence-specific enhancement, and this increased inhibition is suppressed by fear learning but is not restored by extinction training. This altered plasticity during adolescence overlapped with a reduction in calcium-permeable glutamate receptors in SSTINs.

Conclusions

The adolescence-specific plasticity in the SSTINs might play a role in fear extinction suppression during adolescence in mice.

Section snippets

Animals

The following mouse lines were purchased from Jackson Laboratory (Bar Harbor, ME) and subsequently bred in the Skirball division of New York University Medical School animal facility: B6 PVcre (017320, C57BL/6J), sttm2.1(cre)Zjh/J (013044, C57BL/6/129S4SvJae/C57BL/6J), Ai32(RCL-ChR2(H134R)/ EYFP) (024109, C57BL/6J), B6.Cg-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze/J (007914, C57BL/6J), and GAD67/GAD67-EGFP (G42, 007677, BALBc/C57BL/6J) mice. PV-channelrhodopsin-2 (PV-ChR2) mice were generated from

Suppression of Fear Extinction in Adolescent Mice

To compare FE in preadolescent, adolescent, and adult mice, we have pooled together behavioral data from PV-ChR2 (Supplemental Figure S1) and SST-ChR2 mice (Supplemental Figure S2). There were 3 treatment groups: TA, FC, and FE. In preadolescent mice, FC resulted in a robust freezing behavior compared with the TA group (Figure 1A). Furthermore, FE caused a significant reduction in freezing compared with the FC group (Figure 1A). Similar to the preadolescent group, adolescent mice exhibited a

Discussion

Our current study reports the changes in the membrane properties, glutamatergic input, and GABAergic output of PVINs and SSTINs in the IL-mPFC during the transition from preadolescence to adulthood in mice. While PVINs undergo a protracted development and reach maturity only by adulthood, SSTINs are developed early but exhibit an adolescence-specific GABAergic plasticity. The surge in SSTIN-mediated inhibition of pyramidal neurons during adolescence and an irreversible suppression of this

Acknowledgments and Disclosures

This work was supported by National Institutes of Health Grant No. HD076914 (to IN).

The authors report no biomedical financial interests or potential conflicts of interest.

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