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

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 options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Westerink, R.H., Beekwilder, J.P. & Wadman, W.J. Differential alterations of synaptic plasticity in dentate gyrus and CA1 hippocampal area of calbindin-D28K knockout mice. Brain Res. 1450, 1–10 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. 2

    Molinari, S. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5

    Ábrahám, H. 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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  6. 6

    Maglóczky, Z., Halász, P., Vajda, J., Czirják, S. & Freund, T.F. Loss of calbindin-D28K immunoreactivity from dentate granule cells in human temporal lobe epilepsy. Neuroscience 76, 377–385 (1997).

    PubMed  Article  PubMed Central  Google Scholar 

  7. 7

    Iacopino, A.M. & Christakos, S. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8

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

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9

    Palop, J.J. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10

    Karádi, K. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  11. 11

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12

    Sanchez, P.E. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13

    Klapstein, G.J. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14

    Jouvenceau, A. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15

    Brini, M., Calì, T., Ottolini, D. & Carafoli, E. Neuronal calcium signaling: function and dysfunction. Cell. Mol. Life Sci. 71, 2787–2814 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16

    Mucke, L. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17

    Palop, J.J. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

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

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Robison, A.J. & Nestler, E.J. Transcriptional and epigenetic mechanisms of addiction. Nat. Rev. Neurosci. 12, 623–637 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24

    Carter, D.S., Harrison, A.J., Falenski, K.W., Blair, R.E. & DeLorenzo, R.J. Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus. Epilepsy Res. 79, 213–223 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25

    Jenuwein, T. & Allis, C.D. Translating the histone code. Science 293, 1074–1080 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26

    Peng, Z. & Houser, C.R. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27

    Kesner, R.P., Taylor, J.O., Hoge, J. & Andy, F. Role of the dentate gyrus in mediating object-spatial configuration recognition. Neurobiol. Learn. Mem. 118, 42–48 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  28. 28

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29

    Ma, T. et al. Suppression of eIF2α kinases alleviates Alzheimer's disease–related plasticity and memory deficits. Nat. Neurosci. 16, 1299–1305 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Brown, P.H., Kim, S.H., Wise, S.C., Sabichi, A.L. & Birrer, M.J. Dominant-negative mutants of cJun inhibit AP-1 activity through multiple mechanisms and with different potencies. Cell Growth Differ. 7, 1013–1021 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. 33

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

    PubMed  Article  PubMed Central  Google Scholar 

  34. 34

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Nägerl, U.V. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  36. 36

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

    Article  Google Scholar 

  37. 37

    Mattson, M.P., Rychlik, B., Chu, C. & Christakos, S. Evidence for calcium-reducing and excito-protective roles for the calcium-binding protein calbindin-D28k in cultured hippocampal neurons. Neuron 6, 41–51 (1991).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38

    Lopez-Meraz, M.L., Wasterlain, C.G., Rocha, L.L., Allen, S. & Niquet, J. Vulnerability of postnatal hippocampal neurons to seizures varies regionally with their maturational stage. Neurobiol. Dis. 37, 394–402 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39

    Kurushima, H. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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

Authors

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.

Corresponding author

Correspondence to Jeannie Chin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading