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Reductions in synaptic proteins and selective alteration of prepulse inhibition in male C57BL/6 mice after postnatal administration of a VIP receptor (VIPR2) agonist

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Abstract

Rationale

An abundance of genetic and epidemiologic evidence as well as longitudinal neuroimaging data point to developmental origins for schizophrenia and other mental health disorders. Recent clinical studies indicate that microduplications of VIPR2, encoding the vasoactive intestinal peptide (VIP) receptor VPAC2, confer significant risk for schizophrenia and autism spectrum disorder. Lymphocytes from patients with these mutations exhibited higher VIPR2 gene expression and VIP responsiveness (cAMP induction), but mechanisms by which overactive VPAC2 signaling may lead to these psychiatric disorders are unknown.

Objectives

We subcutaneously administered the highly selective VPAC2 receptor agonist Ro 25-1553 to C57BL/6 mice from postnatal day 1 (P1) to P14 to determine if overactivation of VPAC2 receptor signaling during postnatal brain maturation affects synaptogenesis and selected behaviors.

Results

Western blot analyses on P21 revealed significant reductions of synaptophysin and postsynaptic density protein 95 (PSD-95) in the prefrontal cortex, but not in the hippocampus in Ro 25-1553-treated mice. The same postnatally restricted treatment resulted in a disruption in prepulse inhibition of the acoustic startle measured in adult mice. No effects were observed in open-field locomotor activity, sociability in the three-chamber social interaction test, or fear conditioning or extinction.

Conclusion

Overactivation of the VPAC2 receptor in the postnatal mouse results in a reduction in synaptic proteins in the prefrontal cortex and selective alterations in prepulse inhibition. These findings suggest that the VIPR2-linkage to mental health disorders may be due in part to overactive VPAC2 receptor signaling during a critical time of synaptic maturation.

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Acknowledgments

We thank Dr. Felix E. Schweizer (UCLA) and Dr. Thomas J. O’Dell (UCLA) for their kind gifts of anti-synaptophysin and anti-PSD-95 antibodies, respectively. This study was supported in part by grants from Simons Foundation, Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (Grant No. S2603, Japan) and National Institutes of Health (MH098506 and HD04612).

Conflicts of interest

The authors state no conflicts of interest.

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Authors and Affiliations

  1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, 635 Charles E. Young Drive South, Los Angeles, CA, 90095, USA

    Yukio Ago, Michael C. Condro, Cristina A. Ghiani, Michael S. Fanselow & James A. Waschek

  2. Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan

    Yukio Ago

  3. INSERM-Unité Mixte de Recherche U905-IRIB, Université de Rouen, 76183, Rouen Cedex, France

    Yossan-Var Tan

  4. Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, 90095, USA

    Christopher S. Colwell

  5. Department of Psychology, Brain Research Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA

    Jesse D. Cushman & Michael S. Fanselow

  6. Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan

    Hitoshi Hashimoto

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  1. Yukio Ago
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  2. Michael C. Condro
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  3. Yossan-Var Tan
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  4. Cristina A. Ghiani
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  8. Hitoshi Hashimoto
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  9. James A. Waschek
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Correspondence to James A. Waschek.

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Ago, Y., Condro, M.C., Tan, YV. et al. Reductions in synaptic proteins and selective alteration of prepulse inhibition in male C57BL/6 mice after postnatal administration of a VIP receptor (VIPR2) agonist. Psychopharmacology 232, 2181–2189 (2015). https://doi.org/10.1007/s00213-014-3848-z

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