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Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression

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Abstract

Rationale

A number of studies have associated reduced Akt1 expression with vulnerability for schizophrenia. Although mice with deletion of a single copy of the Akt1 gene (Akt1+/−) show reduced Akt1 expression relative to wild-type (WT) animals, the extent to which these mice show schizophrenia-like phenotypic changes and/or increased susceptibility to epigenetic or non-genetic factors related to schizophrenia is unknown.

Objectives

Mutant mice were assessed on electroencephalographic/event-related potential (EEG/ERP) and behavioral (acoustic startle and pre-pulse inhibition) measures relevant to schizophrenia. Mice were also assessed following exposure to the NMDA receptor antagonist ketamine, a potent psychotomimetic drug, in order to assess the role of reduced Akt1 expression as a vulnerability factor for schizophrenia. Methods Akt1+/−, Akt1−/−, and WT mice received a series of paired-click, white noise stimuli, following ketamine (50 mg/kg) and saline injections. EEG was analyzed for ERPs and event-related power. Akt1+/− and WT mice were also assessed on PPI following ketamine (50 mg/kg) or saline injection.

Results

Akt1+/− and Akt1−/− mice displayed reduced amplitude of the P20 component of the ERP to the first click of a paired-click stimulus, as well as reduced S1–S2 difference for P20 and N40 components, following ketamine. Mutant mice also showed increased reduction in gamma synchrony and theta suppression following ketamine. Akt1+/− mice displayed reduced pre-pulse inhibition.

Conclusions

Reduced genetic expression of Akt1 facilitated ketamine-induced changes of EEG and behavior in mice, suggesting that reduced Akt1 expression can serve as a vulnerability factor for schizophrenia.

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Acknowledgements

We are grateful to Tiffany Hill-Smith for expert technical assistance. This study was supported by NIDA grant 5R01DA023210-02 to Steven J. Siegel and by USPHS grant MH 86599 to Irwin Lucki. None of the authors have a financial relationship with the organizations that sponsored the research outlined in the present manuscript.

Steven J. Siegel has received grants from Astellas, AstraZeneca, Abbott, NuPathe, Pfizer, and GlaxoSmithKline that are unrelated to the content of this manuscript. Robert Featherstone has received grant support from Astellas that is unrelated to the content of this manuscript. Steven Siegel has served as a consultant to Abbott, NuPathe, and Lundbeck.

The experiments described in this manuscript comply with the current laws of the USA.

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Authors and Affiliations

  1. Department of Psychiatry, Translational Neuroscience Program, School of Medicine, University of Pennsylvania, 125 South 31st Street, Philadelphia, PA, 19104, USA

    Robert E. Featherstone, Valerie M.Tatard-Leitman, Jimmy D. Suh, Robert Lin & Steven J. Siegel

  2. Department of Psychiatry, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Irwin Lucki

  3. Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Irwin Lucki

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  1. Robert E. Featherstone
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  2. Valerie M.Tatard-Leitman
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  3. Jimmy D. Suh
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  4. Robert Lin
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  5. Irwin Lucki
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  6. Steven J. Siegel
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Corresponding author

Correspondence to Robert E. Featherstone.

Additional information

This study was supported by NIDA grant 5R01DA023210-02 to Steven J. Siegel and by USPHS grant MH 86599 to Irwin Lucki.

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Featherstone, R.E., M.Tatard-Leitman, V., Suh, J.D. et al. Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression. Psychopharmacology 227, 639–649 (2013). https://doi.org/10.1007/s00213-013-2997-9

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