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Calcyon upregulation in adolescence impairs response inhibition and working memory in adulthood

Molecular Psychiatry volume 16, pages 672–684 (2011)Cite this article

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Abstract

Calcyon regulates activity-dependent internalization of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors and long-term depression of excitatory synapses. Elevated levels of calcyon are consistently observed in brains from schizophrenic patients, and the calcyon gene is associated with attention-deficit hyperactivity disorder. Executive function deficits are common to both disorders, and at least for schizophrenia, the etiology appears to involve both heritable and neurodevelopmental factors. Here, we show with calcyon-overexpressing CalOE transgenic mice that lifelong calcyon upregulation impairs executive functions including response inhibition and working memory, without producing learning and memory deficits in general. As response inhibition and working memory, as well as the underlying neural circuitry, continue to mature into early adulthood, we functionally silenced the transgene during postnatal days 28–49, a period corresponding to adolescence. Remarkably, the response inhibition and working memory deficits including perseverative behavior were absent in adult CalOE mice with the transgene silenced in adolescence. Suppressing the calcyon transgene in adulthood only partially rescued the deficits, suggesting calcyon upregulation in adolescence irreversibly alters development of neural circuits supporting mature response inhibition and working memory. Brain regional immunoblots revealed a prominent downregulation of AMPA GluR1 subunits in hippocampus and GluR2/3 subunits in hippocampus and prefrontal cortex of the CalOE mice. Silencing the transgene in adolescence prevented the decrease in hippocampal GluR1, further implicating altered fronto-hippocampal connectivity in the executive function deficits observed in the CalOE mice. Treatments that mitigate the effects of high levels of calcyon during adolescence could preempt adult deficits in executive functions in individuals at risk for serious mental illness.

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Acknowledgements

We thank Dr Sang Lee, Medical College of Wisconsin for the GluR plasmids, Drs Lynn Selemon, David Blake, Philip Wang and Jay Hegde for their comments on the manuscript, Kyle Layman, Nita Vakil and Jonathan Bean for technical support, and Dr Lin Mei for use of the EthoVision XT software. This work was supported by DoD Concept Award PT0713 and MCG PSRP Grant (CB), and MCG start-up funds and NIH Grant 1R21MH083188 (AV).

Author contributions: NM performed protein interaction studies, KB performed and quantified immunohistochemical studies, AV performed and analyzed behavioral experiments, and CB performed immunoblots and wrote the manuscript. AV and CB co-conceived the study.

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Authors and Affiliations

  1. Department of Neurology, Georgia Health Sciences University, Augusta, GA, USA

    A Vazdarjanova & K Bunting

  2. Brain Discovery Institute, Georgia Health Sciences University, Augusta, GA, USA

    A Vazdarjanova, K Bunting & N Muthusamy

  3. Department of Pharmacology and Toxicology, Georgia Health Sciences University, Augusta, GA, USA

    N Muthusamy & C Bergson

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  1. A Vazdarjanova
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  2. K Bunting
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Correspondence to A Vazdarjanova or C Bergson.

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Vazdarjanova, A., Bunting, K., Muthusamy, N. et al. Calcyon upregulation in adolescence impairs response inhibition and working memory in adulthood. Mol Psychiatry 16, 672–684 (2011). https://doi.org/10.1038/mp.2011.14

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