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Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits

Nature Medicine volume 23, pages 1377–1383 (2017)Cite this article

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Abstract

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition1,2,3, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures4,5,6,7. In Alzheimer's disease (AD) and epilepsy, both of which are accompanied by recurrent seizures8, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG)4,9,10. However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of ΔFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of ΔFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by ΔFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures.

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Figure 1: Epigenetic regulation of Calb1 in the hippocampus of APP and pilocarpine-treated mice.
Figure 2: ΔFosB mediates transcriptional repression of Calb1 expression and causes spatial memory deficits.
Figure 3: Both blockade of ΔFosB signaling and direct rescue of calbindin expression ameliorate spatial memory deficits in APP mice.
Figure 4: Increased hippocampal ΔFosB expression corresponds with decreased calbindin expression in human individuals diagnosed with MCI, AD, or TLE.

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Acknowledgements

We thank R. Jagirdar for helpful comments on the manuscript. This work was supported by the Margaret Q. Landenberger Research Foundation (J.C.), the Hassel Family Foundation (J.C.), National Institutes of Health grant NS085171 (J.C.), F30-AG048710 (J.C.Y.), AG051848, BX003040, AG0051839, and AG005131 (R.A.R.), and the New York State Office of Mental Health (H.E.S., J.J.F.).

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Authors and Affiliations

  1. Department of Neuroscience and Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    Jason C You, Kavitha Muralidharan, Iraklis Petrof, Mark S Pyfer, Brian F Corbett, Xiaohong Zhang & Jeannie Chin

  2. Department of Neuroscience, Memory & Brain Research Center, Baylor College of Medicine, Houston, Texas, USA

    Jason C You, Kavitha Muralidharan, Jin W Park, Yi Zheng & Jeannie Chin

  3. Department of Neuroscience and Physiology and Department of Psychiatry, New York University School of Medicine, New York, New York, USA

    John J LaFrancois & Helen E Scharfman

  4. Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA

    Carrie A Mohila

  5. Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA

    Daniel Yoshor

  6. Department of Neurosciences, University of California San Diego School of Medicine, La Jolla, California, USA

    Robert A Rissman

  7. VA San Diego Healthcare System, San Diego, California, USA

    Robert A Rissman

  8. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Eric J Nestler

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Contributions

J.C.Y. and J.C. conceived the project. J.C.Y., X.Z., E.J.N., H.E.S., and J.C. designed the experiments. J.C.Y., M.S.P., I.P., K.M., B.F.C., J.J.F., Y.Z., J.W.P., H.E.S., and J.C. performed the experiments and analyzed the data. C.A.M. and D.Y. collected and analyzed specimens from patients with epilepsy. R.A.R. provided fixed AD brain samples and clinical information. All authors discussed results, and J.C.Y., R.A.R., H.E.S., and J.C. wrote the manuscript.

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Correspondence to Jeannie Chin.

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You, J., Muralidharan, K., Park, J. et al. Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits. Nat Med 23, 1377–1383 (2017). https://doi.org/10.1038/nm.4413

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