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PMID: 16251434 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Impaired regulation of thalamic pacemaker channels through an imbalance of subunit expression in absence epilepsy.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 25 ·No. 43 ·2005-10-26 ·Pages 9871-82

Budde T, Caputi L, Kanyshkova T, Staak R, Abrahamczik C, Munsch T, Pape HC

Abstract

The role of hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channel isoforms and hyperpolarization-activated cation current (Ih) for seizure-related burst firing in thalamocortical (TC) neurons was investigated in a rat genetic model of absence epilepsy [Wistar Albino Glaxo rats, bred in Rijswijk (WAG/Rij)]. Burst discharges in TC neurons locked to seizure activity in vivo were prolonged during blockade of Ih by Cs+ and ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride). In vitro analyses revealed a hyperpolarizing shift of half-maximal Ih activation (Vh) in WAG/Rij (Vh = -93.2 mV) compared with nonepileptic controls [August x Copenhagen-Irish (ACI) (Vh = -88.0 mV)]. This effect is explained by a shift of the responsiveness of Ih to cAMP toward higher concentrations in TC neurons from WAG/Rij, as revealed by application of 8-bromo-cAMP and the phosphodiesterase inhibitor IBMX. During blockade of adenylyl cyclase activity, Ih activation was similar in the two strains, whereas the difference in cAMP responsiveness persisted, thereby voting against different ambient cAMP levels between strains. Increasing the intracellular cAMP level and shifting Ih activation led to a change from burst to tonic firing mode in WAG/Rij but not in ACI rats. Furthermore, HCN1 expression was significantly increased on mRNA and protein levels, with no changes in HCN2-4 expression. In conclusion, there is an increase in HCN1 expression in the epileptic thalamus, associated with a decrease in cAMP responsiveness of Ih in TC neurons and resulting impairment to control the shift from burst to tonic firing, which, in turn, will prolong burst activity after recruitment of Ih during absence seizures.

MeSH Terms
1-Methyl-3-isobutylxanthine/pharmacology 8-Bromo Cyclic Adenosine Monophosphate/pharmacology Action Potentials/drug effects Adenine/analogs & derivatives,pharmacology Animals Blotting, Northern/methods Cerebral Cortex/cytology Cesium/pharmacology Chlorides/pharmacology Cyclic Nucleotide-Gated Cation Channels Disease Models, Animal Dose-Response Relationship, Drug Dose-Response Relationship, Radiation Drug Interactions Electric Stimulation/methods Electroencephalography/methods Enzyme Inhibitors/pharmacology Epilepsy, Absence/genetics,metabolism,physiopathology Female Gene Expression Regulation/drug effects,physiology Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Immunohistochemistry/methods In Situ Hybridization/methods In Vitro Techniques Ion Channels/metabolism Male Membrane Potentials/drug effects,physiology,radiation effects Microinjections Neurons/metabolism Patch-Clamp Techniques/methods Potassium Channels Protein Isoforms/metabolism Pyrimidines/pharmacology RNA, Messenger/biosynthesis Rats Rats, Mutant Strains Rats, Wistar Reverse Transcriptase Polymerase Chain Reaction/methods Thalamus/cytology
Chemicals
Chlorides Cyclic Nucleotide-Gated Cation Channels Enzyme Inhibitors Hcn1 protein, rat Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Ion Channels Potassium Channels Protein Isoforms Pyrimidines RNA, Messenger ICI D2788 9-(tetrahydro-2-furyl)-adenine Cesium 8-Bromo Cyclic Adenosine Monophosphate cesium chloride Adenine 1-Methyl-3-isobutylxanthine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Budde Thomas
Institut für Experimentelle Epilepsieforschung, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany.
Caputi Luigi
Kanyshkova Tatyana
Staak Rainer
Abrahamczik Christian
Munsch Thomas
Pape Hans-Christian
References (55)
55 references, click to expand
  1. Modulation of a pacemaker current through Ca(2+)-induced stimulation of cAMP production.
    Nat Neurosci. 1999 Jul;2(7):634-41 PMID: 10404196
  2. Differential distribution of four hyperpolarization-activated cation channels in mouse brain.
    Biol Chem. 1999 Jul-Aug;380(7-8):975-80 PMID: 10494850
  3. A genetically encoded, fluorescent indicator for cyclic AMP in living cells.
    Nat Cell Biol. 2000 Jan;2(1):25-9 PMID: 10620803
  4. Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS.
    J Neurosci. 2000 Jul 15;20(14):5264-75 PMID: 10884310
  5. Single-cell mRNA expression of HCN1 correlates with a fast gating phenotype of hyperpolarization-activated cyclic nucleotide-gated ion channels (Ih) in central neurons.
    Eur J Neurosci. 2000 Aug;12(8):2685-93 PMID: 10971612
  6. Functional heteromerization of HCN1 and HCN2 pacemaker channels.
    J Biol Chem. 2001 Mar 2;276(9):6069-72 PMID: 11133998
  7. Contribution of GABA(A) and GABA(B) receptors to thalamic neuronal activity during spontaneous absence seizures in rats.
    J Neurosci. 2001 Feb 15;21(4):1378-84 PMID: 11160409
  8. Molecular diversity of pacemaker ion channels.
    Annu Rev Physiol. 2001;63:235-57 PMID: 11181956
  9. Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability.
    Nat Med. 2001 Mar;7(3):331-7 PMID: 11231632
  10. Contribution of intralaminar thalamic nuclei to spike-and-wave-discharges during spontaneous seizures in a genetic rat model of absence epilepsy.
    Eur J Neurosci. 2001 Apr;13(8):1537-46 PMID: 11328348
  11. Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide.
    J Gen Physiol. 2001 May;117(5):491-504 PMID: 11331358
  12. MinK-related peptide 1: A beta subunit for the HCN ion channel subunit family enhances expression and speeds activation.
    Circ Res. 2001 Jun 22;88(12):E84-7 PMID: 11420311
  13. Gi- and Gs-coupled receptors up-regulate the cAMP cascade to modulate HCN2, but not HCN1 pacemaker channels.
    Pflugers Arch. 2001 Sep;442(6):928-42 PMID: 11680627
  14. Differential and age-dependent expression of hyperpolarization-activated, cyclic nucleotide-gated cation channel isoforms 1-4 suggests evolving roles in the developing rat hippocampus.
    Neuroscience. 2001;106(4):689-98 PMID: 11682156
  15. 5-HT-receptor-induced changes of the intracellular cAMP level monitored by a hyperpolarization-activated cation channel.
    Pflugers Arch. 2002 Jan;443(3):418-26 PMID: 11810212
  16. Childhood absence epilepsy: genes, channels, neurons and networks.
    Nat Rev Neurosci. 2002 May;3(5):371-82 PMID: 11988776
  17. Developmental febrile seizures modulate hippocampal gene expression of hyperpolarization-activated channels in an isoform- and cell-specific manner.
    J Neurosci. 2002 Jun 1;22(11):4591-9 PMID: 12040066
  18. Assessing the role of Ih channels in synaptic transmission and mossy fiber LTP.
    Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9538-43 PMID: 12093909
  19. Differential Calcium Binding Protein Immunoreactivity Distinguishes Classes of Relay Neurons in Monkey Thalamic Nuclei.
    Eur J Neurosci. 1989 May;1(3):222-246 PMID: 12106154
  20. Activity-dependent regulation of HCN pacemaker channels by cyclic AMP: signaling through dynamic allosteric coupling.
    Neuron. 2002 Oct 24;36(3):451-61 PMID: 12408847
  21. H-channels in epilepsy: new targets for seizure control?
    Trends Pharmacol Sci. 2002 Dec;23(12):552-7 PMID: 12457772
  22. Hyperpolarization-activated cation currents: from molecules to physiological function.
    Annu Rev Physiol. 2003;65:453-80 PMID: 12471170
  23. Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2.
    EMBO J. 2003 Jan 15;22(2):216-24 PMID: 12514127
  24. KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents.
    Pflugers Arch. 2003 Sep;446(6):633-40 PMID: 12856183
  25. Contribution of TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 channels to the control of activity modes in thalamocortical neurons.
    J Neurosci. 2003 Jul 23;23(16):6460-9 PMID: 12878686
  26. Enhanced expression of a specific hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) in surviving dentate gyrus granule cells of human and experimental epileptic hippocampus.
    J Neurosci. 2003 Jul 30;23(17):6826-36 PMID: 12890777
  27. Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotide-gated channels.
    J Biol Chem. 2003 Oct 31;278(44):43781-6 PMID: 12928435
  28. Interactions between membrane conductances underlying thalamocortical slow-wave oscillations.
    Physiol Rev. 2003 Oct;83(4):1401-53 PMID: 14506309
  29. The multiple personalities of h-channels.
    Trends Neurosci. 2003 Oct;26(10):550-4 PMID: 14522148
  30. Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats.
    Behav Genet. 2003 Nov;33(6):635-55 PMID: 14574120
  31. ZD7288 inhibits low-threshold Ca(2+) channel activity and regulates sperm function.
    Biochem Biophys Res Commun. 2003 Nov 7;311(1):187-92 PMID: 14575712
  32. Pacemaker channels in mouse thalamocortical neurones are regulated by distinct pathways of cAMP synthesis.
    J Physiol. 2004 Jan 1;554(Pt 1):111-25 PMID: 14678496
  33. An impaired neocortical Ih is associated with enhanced excitability and absence epilepsy.
    Eur J Neurosci. 2004 Jun;19(11):3048-58 PMID: 15182313
  34. Correction for liquid junction potentials in patch clamp experiments.
    Methods Enzymol. 1992;207:123-31 PMID: 1528115
  35. Seizure-induced plasticity of h channels in entorhinal cortical layer III pyramidal neurons.
    Neuron. 2004 Oct 28;44(3):495-508 PMID: 15504329
  36. Influence of Ca2+-binding proteins and the cytoskeleton on Ca2+-dependent inactivation of high-voltage activated Ca2+ currents in thalamocortical relay neurons.
    Pflugers Arch. 2005 May;450(2):111-22 PMID: 15647929
  37. Formation of heteromeric hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the hippocampus is regulated by developmental seizures.
    Neurobiol Dis. 2005 Jun-Jul;19(1-2):200-7 PMID: 15837575
  38. Adenosine promotes burst activity in guinea-pig geniculocortical neurones through two different ionic mechanisms.
    J Physiol. 1992 Feb;447:729-53 PMID: 1593463
  39. Noradrenergic and serotonergic modulation of a hyperpolarization-activated cation current in thalamic relay neurones.
    J Physiol. 1990 Dec;431:319-42 PMID: 1712844
  40. Fluorescence ratio imaging of cyclic AMP in single cells.
    Nature. 1991 Feb 21;349(6311):694-7 PMID: 1847505
  41. Visualizing unstained neurons in living brain slices by infrared DIC-videomicroscopy.
    Brain Res. 1990 Dec 24;537(1-2):333-6 PMID: 2085783
  42. A quantitative investigation of the neuronal composition of the rat dorsal lateral geniculate nucleus using GABA-immunocytochemistry.
    Neuroscience. 1986 Sep;19(1):101-11 PMID: 3537838
  43. Effects of the neuroleptanalgesic fentanyl-fluanisone (Hypnorm) on spike-wave discharges in epileptic rats.
    Pharmacol Biochem Behav. 1994 Jun;48(2):547-51 PMID: 8090830
  44. Thalamic multiple-unit activity underlying spike-wave discharges in anesthetized rats.
    Brain Res. 1993 May 28;612(1-2):35-40 PMID: 8330210
  45. Queer current and pacemaker: the hyperpolarization-activated cation current in neurons.
    Annu Rev Physiol. 1996;58:299-327 PMID: 8815797
  46. Sleep and arousal: thalamocortical mechanisms.
    Annu Rev Neurosci. 1997;20:185-215 PMID: 9056712
  47. Increased excitability and inward rectification in layer V cortical pyramidal neurons in the epileptic mutant mouse Stargazer.
    J Neurophysiol. 1997 Feb;77(2):621-31 PMID: 9065835
  48. Lack of regulation by intracellular Ca2+ of the hyperpolarization-activated cation current in rat thalamic neurones.
    J Physiol. 1997 Aug 15;503 ( Pt 1):79-85 PMID: 9288676
  49. Periodicity of thalamic synchronized oscillations: the role of Ca2+-mediated upregulation of Ih.
    Neuron. 1998 Mar;20(3):553-63 PMID: 9539128
  50. Intracellular recordings in thalamic neurones during spontaneous spike and wave discharges in rats with absence epilepsy.
    J Physiol. 1998 Jun 1;509 ( Pt 2):449-56 PMID: 9575294
  51. Periodicity of thalamic spindle waves is abolished by ZD7288,a blocker of Ih.
    J Neurophysiol. 1998 Jun;79(6):3284-9 PMID: 9636128
  52. H-current: properties of a neuronal and network pacemaker.
    Neuron. 1998 Jul;21(1):9-12 PMID: 9697847
  53. Postnatal expression pattern of calcium-binding proteins in organotypic thalamic cultures and in the dorsal thalamus in vivo.
    Brain Res Dev Brain Res. 1998 Sep 10;110(1):83-95 PMID: 9733927
  54. Relations between cortical and thalamic cellular activities during absence seizures in rats.
    Eur J Neurosci. 1998 Mar;10(3):1103-12 PMID: 9753178
  55. Real-time patch-cram detection of intracellular cGMP reveals long-term suppression of responses to NO and muscarinic agonists.
    Neuron. 1998 Oct;21(4):895-906 PMID: 9808474
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.2590-05.2005
Published
2005-10-26
Pages
9871-82
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6725576
Subset
IM
Corrections
CommentIn
PMID: 16761070
External Links
PubMed source DOI: 10.1523/JNEUROSCI.2590-05.2005 PMC Full Text View journal details
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