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Adolescent stress leads to glutamatergic disturbance through dopaminergic abnormalities in the prefrontal cortex of genetically vulnerable mice

  • Original Investigation
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Abstract

Background

Stress during the adolescent period influences postnatal maturation and behavioral patterns in adulthood. Adolescent stress-induced molecular and functional changes in neurons are the key clinical features of psychiatric disorders including schizophrenia.

Objective

In the present study, we exposed genetically vulnerable mice to isolation stress to examine the molecular changes in the glutamatergic system involving N-methyl-d-aspartate (NMDA) receptors via dopaminergic disturbance in the prefrontal cortex (PFc).

Results

We report that late adolescent stress in combination with Disrupted-in-Schizophrenia 1 (DISC1) genetic risk elicited alterations in glutamatergic neurons in the PFc, such as increased expression of glutamate transporters, decreased extracellular levels of glutamate, decreased concentration of d-serine, and impaired activation of NMDA-Ca2+/calmodulin kinase II signaling. These changes resulted in behavioral deficits in locomotor activity, forced swim, social interaction, and novelty preference tests. The glutamatergic alterations in the PFc were prevented if the animals were treated with an atypical antipsychotic drug clozapine and a dopamine D1 agonist SKF81297, which suggests that the activation of dopaminergic neurons is involved in the regulation of the glutamatergic system.

Conclusion

Our results suggest that adolescent stress combined with dopaminergic abnormalities in the PFc of genetically vulnerable mice induces glutamatergic disturbances, which leads to behavioral deficits in the young adult stage.

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Abbreviations

CTL:

Control

DM:

Disease model

DCS:

D-cycloserine

METH:

Methamphetamine

SKF:

SKF81297

TBOA:

DL-threo-β-benzyloxyaspartate

MPC:

5-Methylpyrazole-3-carboxylic acid

CLZ:

Clozapine

PFc:

Prefrontal cortex

NMDA:

N-methyl-d-aspartate

NR1:

NMDA receptor subunit 1

CaMK II:

Ca2+/calmodulin kinase II

TH:

Tyrosine hydroxylase

D2R:

Dopamine D2 receptor

NAc:

Nucleus accumbens

PCP:

Phencyclidine

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Acknowledgements

We thank Prof. A. Sawa, Johns Hopkins University, for critical reading and discussion of the manuscript; Prof. T. Yoshio, T. Izawa, and K. Sakaki, Toho University, for their technical assistance on HPLC analyses; and Editage (www.editage.jp) for English language editing.

This work was supported by the “Academic Frontier” Project for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), Research on Regulatory Science of Pharmaceuticals and Medical Devices and Risk of Chemical Substances from the Ministry of Health, Labour and Welfare of Japan (MHLW), JSPS grants 19659292, 20390073, 22659213, 22248033, 26460240, and 17H04252, and Research Grant from the SRF (T.N.); by NIH grants DA-040127 and K99MH-094408, NARSAD, JSPS grants 20007152 and 23-639, and JST PRESTO JPMJPR14M6 (M.N.); by Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development (AMED) and Scientific Research on Innovative Areas, “Glial assembly: a new regulatory machinery of brain function and disorders” (N.O.); by JSPS grant 16K10195, and Research Grant from the SRF (A.M.).

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Authors and Affiliations

  1. Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, 468-8503, Japan

    Yurie Matsumoto, Minae Niwa, Akihiro Mouri & Toshitaka Nabeshima

  2. Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, 466-8560, Japan

    Yurie Matsumoto, Minae Niwa & Norio Ozaki

  3. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Minae Niwa

  4. Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Science, Toyoake, 470-1192, Japan

    Akihiro Mouri & Toshitaka Nabeshima

  5. NPO Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-0069, Japan

    Akihiro Mouri, Yukihiro Noda & Toshitaka Nabeshima

  6. Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, 468-8503, Japan

    Yukihiro Noda

  7. Department of Analytical Chemistry, Faculty of Pharmaceutical Science, Toho University, Chiba, 274-8510, Japan

    Takeshi Fukushima

  8. Aino University, Ibaragi, Osaka, 567-0012, Japan

    Toshitaka Nabeshima

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  1. Yurie Matsumoto
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Correspondence to Minae Niwa or Toshitaka Nabeshima.

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All animal procedures were in accordance with guidelines for the care and use of laboratory animals issued by the National Institutes of Health, Japanese Pharmacological Society, and Meijo University.

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Matsumoto, Y., Niwa, M., Mouri, A. et al. Adolescent stress leads to glutamatergic disturbance through dopaminergic abnormalities in the prefrontal cortex of genetically vulnerable mice. Psychopharmacology 234, 3055–3074 (2017). https://doi.org/10.1007/s00213-017-4704-8

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