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Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites

Abstract

The dendrites of pyramidal neurons have markedly different electrical properties from those of the soma, owing to the non-uniform distribution of voltage-gated ion channels in dendrites. It is thus possible that drugs acting on ion channels might preferentially alter dendritic, but not somatic, excitability. Using dendritic and somatic whole-cell and cell-attached recordings in rat hippocampal slices, we found that the anticonvulsant lamotrigine selectively reduced action potential firing from dendritic depolarization, while minimally affecting firing at the soma. This regional and input-specific effect resulted from an increase in the hyperpolarization-activated cation current (Ih), a voltage-gated current present predominantly in dendrites. These results demonstrate that neuronal excitability can be altered by drugs acting selectively on dendrites, and suggest an important role for Ih in controlling dendritic excitability and epileptogenesis.

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Figure 1: Lamotrigine (LTG) selectively lowered dendritic excitability.
Figure 2: LTG, but not phenytoin or carbamazepine, lowered dendritic excitability.
Figure 3: LTG decreased AP firing elicited from the dendrites without affecting AP back-propagation in dendrites.
Figure 4: LTG decreased dendritic excitability by increasing activation of Ih.
Figure 5: LTG causes a depolarizing shift in Ih activation.
Figure 6: Ih activation decreased AP firing in a computational model.
Figure 7: LTG decreased synaptic activation of pyramidal neurons by reducing temporal summation in a frequency-dependent manner.

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References

  1. Hausser, M., Spruston, N. & Stuart, G. J. Diversity and dynamics of dendritic signaling. Science 290, 739–744 (2000).

    Article  CAS  PubMed Central  Google Scholar 

  2. Johnston, D., Magee, J. C., Colbert, C. M. & Christie, B. R. Active properties of neuronal dendrites. Annu. Rev. Neurosci. 19, 165–186 (1996).

    Article  CAS  Google Scholar 

  3. Magee, J., Hoffman, D., Colbert, C. & Johnston, D. Electrical and calcium signaling in dendrites of hippocampal pyramidal neurons. Annu. Rev. Physiol. 60, 327–346 (1998).

    Article  CAS  PubMed Central  Google Scholar 

  4. Poolos, N. P. & Johnston, D. Calcium-activated potassium conductances contribute to action potential repolarization at the soma but not the dendrites of hippocampal CA1 pyramidal neurons. J. Neurosci. 19, 5205–5212 (1999).

    Article  CAS  PubMed Central  Google Scholar 

  5. Johnston, D. et al. Dendritic potassium channels in hippocampal pyramidal neurons. J. Physiol. (Lond.) 525, 75–81 (2000).

    Article  CAS  Google Scholar 

  6. Messenheimer, J. in The Treatment of Epilepsy: Principles and Practice (ed. Wyllie, E.) 899–905 (Williams and Wilkins, Baltimore, 1996).

    Google Scholar 

  7. Calabrese, J. R. Lamotrigine and the treatment of bipolar disorder. Introduction. Eur Neuropsychopharmacol. 9 (Suppl. 4), S107–108 (1999).

    Article  CAS  PubMed Central  Google Scholar 

  8. White, H. S. in The Epilepsies 2 (eds. Porter, R. J. & Chadwick, D.) 1–30 (Butterworth-Heinemann, Boston, 1997).

    Google Scholar 

  9. Kuo, C.-C. & Lu, L. Characterization of lamotrigine inhibition of Na+ channels in rat hippocampal neurons. Br. J. Pharmacol. 121, 1231–1238 (1997).

    Article  CAS  PubMed Central  Google Scholar 

  10. Xie, X., Lancaster, B., Peakman, T. & Garthwaite, J. Interaction of the antiepileptic drug lamotrigine with recombinant rat brain type IIA Na+ channels and with native Na+ channels in rat hippocampal neurons. Pflugers Arch. 430, 437–446 (1995).

    Article  CAS  PubMed Central  Google Scholar 

  11. Colbert, C. M., Magee, J. C., Hoffman, D. A. & Johnston, D. Slow recovery from inactivation of Na+ channels underlies the activity-dependent attenuation of dendritic action potentials in hippocampal CA1 pyramidal neurons. J. Neurosci. 17, 6512–6521 (1997).

    Article  CAS  Google Scholar 

  12. Golding, N. L. & Spruston, N. Dendritic sodium spikes are variable triggers of axonal action potentials in hippocampal CA1 pyramidal neurons. Neuron 21, 1189–1200 (1998).

    Article  CAS  Google Scholar 

  13. Stuart, G., Spruston, N., Sakmann, B. & Hausser, M. Action potential initiation and backpropagation in neurons of the mammalian CNS. Trends Neurosci. 20, 125–131 (1997).

    Article  CAS  Google Scholar 

  14. Santoro, B. et al. Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS. J. Neurosci. 20, 5264–5275 (2000).

    Article  CAS  PubMed Central  Google Scholar 

  15. Pape, H.-C. Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu. Rev. Physiol. 58, 299–327 (1996).

    Article  CAS  PubMed Central  Google Scholar 

  16. Magee, J. C. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J. Neurosci. 18, 7613–7624 (1998).

    Article  CAS  Google Scholar 

  17. Stuart, G. & Spruston, N. Determinants of voltage attenuation in neocortical pyramidal neuron dendrites. J. Neurosci. 18, 3501–3510 (1998).

    Article  CAS  Google Scholar 

  18. Magee, J. C. Dendritic Ih normalizes temporal summation in hippocampal CA1 neurons. Nat. Neurosci. 2, 508–514 (1999).

    Article  CAS  PubMed Central  Google Scholar 

  19. Harris, N. C. & Constanti, A. Mechanism of block by ZD 7288 of the hyperpolarization-activated inward rectifying current in guinea pig substantia nigra neurons in vitro. J. Neurophysiol. 74, 2366–2378 (1995).

    Article  CAS  PubMed Central  Google Scholar 

  20. Chen, S., Wang, J. & Siegelbaum, S. A. Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide. J. Gen. Physiol. 117, 491–504 (2001).

    Article  CAS  PubMed Central  Google Scholar 

  21. Fiala, J. C. & Harris, K. M. in Dendrites (eds. Stuart, G., Spruston, N. & Hausser, M.) (Oxford University Press, Oxford, 1999).

    Google Scholar 

  22. Stefani, A., Spadoni, F., Siniscalchi, A. & Bernardi, G. Lamotrigine inhibits Ca2+ currents in cortical neurons: functional implications. Eur. J. Pharmacol. 307, 113–116 (1996).

    Article  CAS  PubMed Central  Google Scholar 

  23. Wang, S. J., Sihra, T. S. & Gean, P. W. Lamotrigine inhibition of glutamate release from isolated cerebrocortical nerve terminals (synaptosomes) by suppression of voltage-activated calcium channel activity. Neuroreport 12, 2255–2258 (2001).

    Article  CAS  PubMed Central  Google Scholar 

  24. Coulter, D. A. Antiepileptic drug cellular mechanisms of action: where does lamotrigine fit in? J. Child Neurol. 12 (Suppl.1), 2–9 (1997).

    Article  Google Scholar 

  25. Chen, K. et al. Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability. Nat. Med. 7, 331–337 (2001).

    Article  CAS  PubMed Central  Google Scholar 

  26. Lupica, C. R., Bell, J. A., Hoffman, A. F. & Watson, P. L. Contribution of the hyperpolarization-activated current (Ih) to membrane potential and GABA release in hippocampal interneurons. J. Neurophysiol. 86, 261–268 (2001).

    Article  CAS  PubMed Central  Google Scholar 

  27. Beaumont, V. & Zucker, R. S. Enhancement of synaptic transmission by cyclic AMP modulation of presynaptic Ih channels. Nat. Neurosci. 3, 133–141 (2000).

    Article  CAS  PubMed Central  Google Scholar 

  28. Shorvon, S. D. Handbook of Epilepsy Treatment (Blackwell, Oxford, 2000).

    Google Scholar 

  29. Hines, M. L. & Carnevale, N. T. The NEURON simulation environment. Neural Comput. 9, 1179–1209 (1997).

    Article  CAS  Google Scholar 

  30. Migliore, M., Hoffman, D. A., Magee, J. C. & Johnston, D. Role of an A-type K+ conductance in the back-propagation of action potentials in the dendrites of hippocampal pyramidal neurons. J. Comput. Neurosci. 7, 5–15 (1999).

    Article  CAS  PubMed Central  Google Scholar 

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Acknowledgements

We thank R. Gray for writing the data acquisition software and providing help in all phases of experimentation and data analysis. We also thank R. Chitwood, C. Bernard and A. Frick for reading earlier versions of the manuscript. Research was supported by the National Institutes of Health (N.P.P. and D.J.), the National Institute of Deafness and Other Communication Disorders Human Brain Project (M.M.), the National Epifellows Foundation (N.P.P.) and the Hankamer Foundation (D.J.).

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Correspondence to Daniel Johnston.

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Dr. Poolos has been a member of the GlaxoSmithKline Speaker's Bureau.

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Poolos, N., Migliore, M. & Johnston, D. Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nat Neurosci 5, 767–774 (2002). https://doi.org/10.1038/nn891

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