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Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α

Molecular Psychiatry volume 22, pages 1096–1109 (2017)Cite this article

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Abstract

CACNA1C, encoding the Cav1.2 subunit of L-type Ca2+ channels, has emerged as one of the most prominent and highly replicable susceptibility genes for several neuropsychiatric disorders. Cav1.2 channels play a crucial role in calcium-mediated processes involved in brain development and neuronal function. Within the CACNA1C gene, disease-associated single-nucleotide polymorphisms have been associated with impaired social and cognitive processing and altered prefrontal cortical (PFC) structure and activity. These findings suggest that aberrant Cav1.2 signaling may contribute to neuropsychiatric-related disease symptoms via impaired PFC function. Here, we show that mice harboring loss of cacna1c in excitatory glutamatergic neurons of the forebrain (fbKO) that we have previously reported to exhibit anxiety-like behavior, displayed a social behavioral deficit and impaired learning and memory. Furthermore, focal knockdown of cacna1c in the adult PFC recapitulated the social deficit and elevated anxiety-like behavior, but not the deficits in learning and memory. Electrophysiological and molecular studies in the PFC of cacna1c fbKO mice revealed higher E/I ratio in layer 5 pyramidal neurons and lower general protein synthesis. This was concurrent with reduced activity of mTORC1 and its downstream mRNA translation initiation factors eIF4B and 4EBP1, as well as elevated phosphorylation of eIF2α, an inhibitor of mRNA translation. Remarkably, systemic treatment with ISRIB, a small molecule inhibitor that suppresses the effects of phosphorylated eIF2α on mRNA translation, was sufficient to reverse the social deficit and elevated anxiety-like behavior in adult cacna1c fbKO mice. ISRIB additionally normalized the lower protein synthesis and higher E/I ratio in the PFC. Thus this study identifies a novel Cav1.2 mechanism in neuropsychiatric-related endophenotypes and a potential future therapeutic target to explore.

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Acknowledgements

This work was supported by The Hartwell Foundation (AMR), the Weill Cornell Autism Research Program (AMR), the Weill Cornell Medicine Postdoctoral Fellowship (ZDK), the National Institutes of Health (5R01DA029122 to AMR; 5 R00 MH095825 05 and 1 R01 MH110553 01 to NVDMG), Leon Levy Foundation (NVDMG), and Citizens United for Research in Epilepsy (CURE; NVDMG). We thank Dr Jacqueline Crawley for technical assistance with establishing the social interaction behavioral apparatus and procedure in our laboratory. We thank Drs Eric Klann, Aditi Bhattacharya, Alexandra Cohen and Anni Lee for technical assistance with establishing the water-based Y-maze behavioral paradigm in our laboratory. We thank Dr Andrew Pieper for critical reading of the manuscript and Dr Héctor De Jesús-Cortés for his comments on the figures.

Author contributions

ZDK and AMR contributed to the experimental design, data interpretation and wrote the paper. AC and NVDMG performed electrophysiological experiments and analyzed data. ZDK performed stereotaxic surgeries and analyzed data. ZDK and DKF conducted molecular and behavioral experiments. BR conducted molecular experiments. RCR and MB conducted behavioral experiments. MJG conducted electron microscopy experiments. All authors discussed and commented on the manuscript.

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Authors and Affiliations

  1. Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA

    Z D Kabir, D K Fischer, R C Rice, B K Rizzo, M Byrne & A M Rajadhyaksha

  2. Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA

    Z D Kabir, D K Fischer, R C Rice, M Byrne & A M Rajadhyaksha

  3. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA

    A Che, M J Glass, N V De Marco Garcia & A M Rajadhyaksha

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  1. Z D Kabir
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Kabir, Z., Che, A., Fischer, D. et al. Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α. Mol Psychiatry 22, 1096–1109 (2017). https://doi.org/10.1038/mp.2017.124

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