Letter | Published:

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

Nature Medicine volume 23, pages 13771383 (2017) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & Differential alterations of synaptic plasticity in dentate gyrus and CA1 hippocampal area of calbindin-D28K knockout mice. Brain Res. 1450, 1–10 (2012).

  2. 2.

    et al. Deficits in memory and hippocampal long-term potentiation in mice with reduced calbindin D28K expression. Proc. Natl. Acad. Sci. USA 93, 8028–8033 (1996).

  3. 3.

    et al. Decrease in calbindin content significantly alters LTP but not NMDA receptor and calcium channel properties. Neuropharmacology 42, 444–458 (2002).

  4. 4.

    et al. Decreased hippocampal expression of calbindin D28K and cognitive impairment in MELAS. J. Neurol. Sci. 317, 29–34 (2012).

  5. 5.

    et al. Degree and pattern of calbindin immunoreactivity in granule cells of the dentate gyrus differ in mesial temporal sclerosis, cortical malformation– and tumor-related epilepsies. Brain Res. 1399, 66–78 (2011).

  6. 6.

    , , , & Loss of calbindin-D28K immunoreactivity from dentate granule cells in human temporal lobe epilepsy. Neuroscience 76, 377–385 (1997).

  7. 7.

    & Specific reduction of calcium-binding protein (28-kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases. Proc. Natl. Acad. Sci. USA 87, 4078–4082 (1990).

  8. 8.

    & Shared cognitive and behavioral impairments in epilepsy and Alzheimer's disease and potential underlying mechanisms. Epilepsy Behav. 26, 343–351 (2013).

  9. 9.

    et al. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease–related cognitive deficits. Proc. Natl. Acad. Sci. USA 100, 9572–9577 (2003).

  10. 10.

    et al. Correlation between calbindin expression in granule cells of the resected hippocampal dentate gyrus and verbal memory in temporal lobe epilepsy. Epilepsy Behav. 25, 110–119 (2012).

  11. 11.

    et al. Tau-dependent Kv4.2 depletion and dendritic hyperexcitability in a mouse model of Alzheimer's disease. J. Neurosci. 35, 6221–6230 (2015).

  12. 12.

    et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc. Natl. Acad. Sci. USA 109, E2895–E2903 (2012).

  13. 13.

    et al. Calbindin-D28k fails to protect hippocampal neurons against ischemia in spite of its cytoplasmic calcium buffering properties: evidence from calbindin-D28k knockout mice. Neuroscience 85, 361–373 (1998).

  14. 14.

    et al. Glutamatergic synaptic responses and long-term potentiation are impaired in the CA1 hippocampal area of calbindin D28k-deficient mice. Synapse 33, 172–180 (1999).

  15. 15.

    , , & Neuronal calcium signaling: function and dysfunction. Cell. Mol. Life Sci. 71, 2787–2814 (2014).

  16. 16.

    et al. High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058 (2000).

  17. 17.

    et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron 55, 697–711 (2007).

  18. 18.

    et al. Incidence and impact of subclinical epileptiform activity in Alzheimer's disease. Ann. Neurol. 80, 858–870 (2016).

  19. 19.

    et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 70, 1158–1166 (2013).

  20. 20.

    & Transcriptional and epigenetic mechanisms of addiction. Nat. Rev. Neurosci. 12, 623–637 (2011).

  21. 21.

    et al. ΔFosB mediates epigenetic desensitization of the c-fos gene after chronic amphetamine exposure. J. Neurosci. 28, 7344–7349 (2008).

  22. 22.

    et al. Experience-dependent induction of hippocampal ΔFosB controls learning. J. Neurosci. 35, 13773–13783 (2015).

  23. 23.

    & Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc. Natl. Acad. Sci. USA 88, 3720–3724 (1991).

  24. 24.

    , , , & Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus. Epilepsy Res. 79, 213–223 (2008).

  25. 25.

    & Translating the histone code. Science 293, 1074–1080 (2001).

  26. 26.

    & Temporal patterns of Fos expression in the dentate gyrus after spontaneous seizures in a mouse model of temporal lobe epilepsy. J. Neurosci. 25, 7210–7220 (2005).

  27. 27.

    , , & Role of the dentate gyrus in mediating object-spatial configuration recognition. Neurobiol. Learn. Mem. 118, 42–48 (2015).

  28. 28.

    et al. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat. Commun. 6, 6606 (2015).

  29. 29.

    et al. Suppression of eIF2α kinases alleviates Alzheimer's disease–related plasticity and memory deficits. Nat. Neurosci. 16, 1299–1305 (2013).

  30. 30.

    , , , & Dominant-negative mutants of cJun inhibit AP-1 activity through multiple mechanisms and with different potencies. Cell Growth Differ. 7, 1013–1021 (1996).

  31. 31.

    et al. Striatal overexpression of ΔJunD resets L-DOPA-induced dyskinesia in a primate model of Parkinson disease. Biol. Psychiatry 66, 554–561 (2009).

  32. 32.

    & Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb. Perspect. Biol. 4, a009886 (2012).

  33. 33.

    et al. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann. Neurol. 72, 184–191 (2012).

  34. 34.

    et al. Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease. Nat. Med. 23, 678–680 (2017).

  35. 35.

    et al. Surviving granule cells of the sclerotic human hippocampus have reduced Ca2+ influx because of a loss of calbindin-D28k in temporal lobe epilepsy. J. Neurosci. 20, 1831–1836 (2000).

  36. 36.

    & Calcium-dependent inactivation of high-threshold calcium currents in human dentate gyrus granule cells. J. Physiol. (Lond.) 509, 39–45 (1998).

  37. 37.

    , , & Evidence for calcium-reducing and excito-protective roles for the calcium-binding protein calbindin-D28k in cultured hippocampal neurons. Neuron 6, 41–51 (1991).

  38. 38.

    , , , & Vulnerability of postnatal hippocampal neurons to seizures varies regionally with their maturational stage. Neurobiol. Dis. 37, 394–402 (2010).

  39. 39.

    et al. Selective induction of ΔFosB in the brain after transient forebrain ischemia accompanied by an increased expression of galectin-1, and the implication of ΔFosB and galectin-1 in neuroprotection and neurogenesis. Cell Death Differ. 12, 1078–1096 (2005).

  40. 40.

    et al. Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 60, 803–817 (2008).

  41. 41.

    et al. Suppression of adult neurogenesis increases the acute effects of kainic acid. Exp. Neurol. 264, 135–149 (2015).

Download references

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.).

Author information

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. Memory & Brain Research Center, Department of Neuroscience, 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

Authors

  1. Search for Jason C You in:

  2. Search for Kavitha Muralidharan in:

  3. Search for Jin W Park in:

  4. Search for Iraklis Petrof in:

  5. Search for Mark S Pyfer in:

  6. Search for Brian F Corbett in:

  7. Search for John J LaFrancois in:

  8. Search for Yi Zheng in:

  9. Search for Xiaohong Zhang in:

  10. Search for Carrie A Mohila in:

  11. Search for Daniel Yoshor in:

  12. Search for Robert A Rissman in:

  13. Search for Eric J Nestler in:

  14. Search for Helen E Scharfman in:

  15. Search for Jeannie Chin in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jeannie Chin.

Supplementary information

PDF files

  1. 1.

    Supplementary Figures

    Supplementary Figures 1–9

  2. 2.

    Life Sciences Reporting Summary

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm.4413