Research Group Cellular Neurophysiology

Head: Dr. Christian Alzheimer, Professor of Physiology

Address:

Institute of Physiology
University of Kiel
Olshausenstr. 40
24098 Kiel
Germany

Telephon:

+49-431-880-2025/2032

FAX:

+49-431-880-5532

email:

c.alzheimer@physiologie.uni-kiel.de

People in the lab

                    Christian                     Alzheimer Barbara Nixdorf-Bergweiler Angelika Klose Karoline Schmidt-Neuenfeldt
Philipp Bergmann Didier Gremelle Tobias Huth Fang Zheng

Current lab members:

Fang Zheng, Ph. D.
Tobias Huth, M. D., Ph. D.
Barbara Nixdorf-Bergweiler, Ph. D.
Philipp Bergmann M. D.
Angelika Klose, M. D.
Karoline Schmidt-Neuenfeldt, M. D. 
Didier Gremelle


MD thesis students:

Nils Jansen

Matthias Nissen

Katja Lammert

Meike Völkel

Kathi Chammas

Unterrichtsmaterial

Integrative Funktionen des ZNS

Skript zum entsprechenden Abschnitt der Hauptvorlesung: PDF-file 700kb

Research Interests

I. Role of activin in hippocampal excitability and plasticity, anxiety-like behavior, and neuroprotection

Activins belong to the transforming growth factor β (TGF β) superfamily and are now recognized as multifunctional regulatory proteins. Whereas we and others have firmly established a neuroprotective role of activin in acute brain injury, it remained unclear whether activin also influences the operation of neuronal circuits under physiological conditions. To explore the functions of activin in normal adult brain, S. Werner and her group at the Institute of Cell Biology (ETH Zurich) generated transgenic mice expressing a dominant-negative mutant of activin receptor IB (dnActRIB) under the control of the CaMKII-α promoter. In hippocampal slices of dnActRIB mice, we found that the NMDA component of glutamatergic neurotransmission was decreased and, as a consequence, synaptic plasticity was impaired, causing a significant reduction in long-term potentiation (LTP) at the Schaffer-CA1 synapse. These data were the first to demonstrate that endogenously produced activin is capable of modulating the performance of the major excitatory synapse in the brain. We have now extended our study to the role of activin at the GABAergic synapse. GABA is the major inhibitory transmitter in the brain and has been implicated in a broad spectrum of physiological functions and disease states, including anxiety and depression. In behavioral tests, disruption of activin receptor signaling produced a low-anxiety phenotype that failed to respond to benzodiazepines. In whole-cell recordings from hippocampal pyramidal cells, enhanced spontaneous GABA release, increased GABA tonus, reduced benzodiazepine sensitivity and augmented GABAB receptor function emerged as likely substrates of the low-anxiety phenotype. These data provide strong evidence that activin influences pre- and postsynaptic components of GABAergic synapses in a highly synergistic fashion. Given the crucial role of GABAergic neurotransmission in emotional states, anxiety and depression, dysfunctions of activin receptor signaling could be involved in affective disorders and drugs affecting this pathway might show promise for psychopharmacological treatment.

References:

  • Tretter YP, Munz B, Hübner G, ten Bruggencate G, Werner S & Alzheimer C: Strong induction of activin expression after hippocampal lesion. Neuroreport 7: 1819-1823, 1996.
  • Chesi A, Rucker F, Tretter YP, ten Bruggencate G & Alzheimer C: Spread of excitation in chronically lesioned hippocampus determined by laser scanning microscopy. Expl Neurol 152:177-187, 1998.
  • Hübner G, Alzheimer C & Werner S: Activin - a novel player in tissue repair processes. Histol Histopathol 14: 295-304, 1999. (Review)
  • Munz B, Hübner G, Tretter YP, Alzheimer C & Werner S: A novel role of activin in inflammation and repair. J Endocrinol 161: 187-193, 1999. (Review)
  • Hertel M, Tretter YP, Alzheimer C & Werner S: Connective tissue growth factor: a novel player in tissue reorganisation after brain injury? Eur J Neurosci 12: 376-380, 2000.
  • Tretter YP, Hertel M, Munz B, ten Bruggencate G, Werner S & Alzheimer C: Induction of activin A is essential for the neuroprotective action of bFGF in vivo. Nature Medicine 6: 812-815, 2000.
  • Alzheimer C and Werner S: Fibroblast Growth Factors and Neuroprotection. In: Alzheimer C (ed.): Molecular and Cellular Biology of Neuroprotection in the CNS. Kluwer Acad Publ, 2002.
  • Hertel M, Braun S, Durka S, Alzheimer C and Werner S: Upregulation and activation of the Nrf-1 transcription factor in the lesioned hippocampus. Eur J Neurosci 15: 1707 - 1711, 2002.
  • Alzheimer C (ed.): Molecular and Cellular Biology of Neuroprotection in the CNS. Kluwer Acad Publ, 2002.
  • Wankell M, Werner Silke, Alzheimer C, and Werner Sabine: The roles of activin in cytoprotection and tissue repair. Ann. N.Y. Acad. Sci. 995:48-58, 2003.
  • Sulyok S, Wankell S, Alzheimer C, and Werner S. Activin: an important regulator of wound repair, fibrosis, and neuroprotection. Mol. Cell. Endocrinol. 225:127-132, 2004.
  • Vorobyov V, Schibaev N, Kovalev G and Alzheimer C. Effects of neurotransmitter agonists on electrocortical activity in the rat kainate model of temporal lobe epilepsy and the modulatory action of basic fibroblast growth factor. Brain Res 1051(1-2):123-136, 2005.
  • Werner S and Alzheimer C: Roles of activin in tissue repair, fibrosis, and inflammatory disease. Cytokine Growth Factor Rev 17: 157-171, 2006.
  • Müller M, Zheng F, Werner S and Alzheimer C. Transgenic mice expressing dominant-negative activin receptor IB in forebrain neurons reveal novel functions of activin at glutamatergic synapses. J Biol Chem 281:29076-29084, 2006.
  • Zheng F, Adelsberger H, Müller MR, Fritschy J-M, Werner S and Alzheimer C: Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior. Mol Psychiat, doi 10.1038/sj.mp.4002131, 2008.

II. Properties and Function of Na and K Channels in CNS Neurons

Using acutely isolated neurons and brain slices, we are investigating properties and functions of sodium currents and inward rectifier potassium currents. In particular, we are studying

  1. how these currents are modulated by various neurotransmitters and -modulators,
  2. how these currents might be involved in CNS disease,
  3. how these currents influence signal processing, and
  4. how the properties of these currents change during postnatal development.

References:

  • Alzheimer C, Schwindt PC and Crill WE: Modal gating of Na+ channels as a mechanism of persistent Na+ current in pyramidal neurons from rat and cat neocortex. J Neurosci 13: 660-673, 1993.
  • Alzheimer C, Schwindt PC and Crill WE: Postnatal development of a persistent Na+ current in pyramidal neurons from rat sensorimotor cortex. J Neurophysiol 69: 290-292, 1993.
  • Alzheimer C: A novel voltage-dependent cation current in rat neocortical neurones. J Physiol Lond. 479: 199-205, 1994.
  • Chao TI and Alzheimer C: Effects of phenytoin on the persistent Na+ current of mammalian CNS neurones. Neuroreport 6: 1778-1780, 1995.
  • Chao TI and Alzheimer C: Do neurones from rat neostriatum express both a TTX-sensitive and a TTX-insensitive slow Na+ current? J Neurophysiol 74: 934-941, 1995.
  • Lipowsky R, Gillessen T and Alzheimer C: Dendritic Na+ channels amplify EPSPs in hippocampal CA1 pyramidal cells. J Neurophysiol 76: 2181-2191, 1996.
  • Mittmann T and Alzheimer C: Muscarinic inhibition of persistent Na+ current in rat neocortical pyramidal neurons. J Neurophysiol 79: 1579-1582, 1998.
  • Gillessen T and Alzheimer C: Amplification of EPSPs by low voltage-activated Ca2+ channels in apical dendrites of rat CA1 pyramidal neurons. J Neurophysiol 77: 1639-1643, 1997.
  • Takigawa T and Alzheimer C: G protein-activated inwardly rectifying K+ (GIRK) currents in dendrites of rat neocortical pyramidal cells. J Physiol (Lond.) 517:385-390, 1999.
  • Takigawa T and Alzheimer C: Variance analysis of current fluctuations of adenosine- and baclofen-activated GIRK channels in dissociated neocortical pyramidal cells. J Neurophysiol 83: 1647-1650, 1999.
  • Brand S, Seeger T and Alzheimer C: Enhancement of persistent Na+ current by sea anemone toxin (ATX II) exerts dual action on hippocampal excitability. Eur J Neurosci 12: 2387-2396, 2000.
  • van Brederode J, Takigawa T and Alzheimer C: GABA-evoked chloride currents do not differ between dendrites and somata of rat neocortical neurons. J Physiol (Lond.) 533: 711-716, 2001.
  • Seeger T and Alzheimer C: Muscarinic activation of inwardly rectifying K+ conductance reduces EPSPs in rat hippocampal CA1 pyramidal cells. J Physiol (Lond.) 535: 383-396, 2001.
  • Sickmann T and Alzheimer C: Agonist-specific maturation of GIRK current reponses in acutely isolated pyramidal neurons of rat neocortex. Brain Res 929: 166-174, 2002.
  • Alzheimer C: Na+ channels and Ca2+ channels of the cell membrane as targets of neuroprotective substances. In: Alzheimer C (ed.): Molecular and Cellular Biology of Neuroprotection in the CNS. Kluwer, Acad Publ, 2002.
  • Takigawa T and Alzheimer C: Phasic and tonic attenuation of EPSPs by inward rectifier K+ channels in rat hippocampal pyramidal cells. J Physiol (Lond.) 539: 67-75, 2002.
  • Takigawa T and Alzheimer C: Interplay between activation of GIRK current and deactivation of I(h) modifies temporal integration of excitatory input in CA1 pyramidal cells. J Neurophysiol 89: 2238-2244, 2003.
  • Sickmann T and Alzheimer C: Short-term desensitization of G protein-activated, inwardly rectifying K (GIRK) currents in pyramidal neurons of rat neocortex. J Neurophysiol 90:2494-2503, 2003.
  • Dominguez D, Tournoy J, Hartmann D, Huth T, Cryns K, Deforce S, Serneels L, Espuny Camacho I, Marjaux E, Craessaerts K, Roebroek AJM, Schwake M, D’Hooge R, Bach P, Kalinke U, Moechars D, Alzheimer C, Reiss K, Saftig P, De Strooper B. Phenotypical and biochemical analysis of BACE1 and BACE2 deficient mice. J Biol Chem 280(35):30797-30806, 2005.
  • Sickmann T, Klose A, Huth T, Alzheimer C. Unexpected suppression of neuronal G protein-activated, inwardly rectifying K+ current by common phospholipase C inhibitor. Neurosci Lett 436: 102-106, 2008.
  • Huth T, Schmidtmayer J, Alzheimer C, Hansen UP. 4-mode gating model of fast inactivation of sodium channel Nav1.2a. Pflügers Arch-Eur J Physiol 457: 103-119, 2008.
  • Klose A, Huth T, Alzheimer C. U73122 Selectively Inhibits Kir3 and BK Channels in a Phospholipase C-Independent Fashion. Mol Pharmacol: doi: 10.1124/mol.108.047837, 2008.
  • Huth T, Schmidt-Neuenfeldt K, Rittger A, Saftig P, Reiss K, Alzheimer C. Non-proteolytic effect of ß-site APP-cleaving enzyme 1 (BACE1) on sodium channel function. Neurobiology of Disease, in press.


III. Muscarinic Modulation of Synaptic Integration and Plasticity

Although muscarinic receptors are known to play central roles in facilitating cognitive functions, it is still not well understood how activation of individual receptor subtypes (M1 - M5) influences the neurobiological mechanisms that are thought to underlie learning and memory at the cellular and network level. Given the lack of muscarinic receptor ligands with a high degree of receptor subtype selectivity, we mainly use muscarinic receptor knock-out mice to elucidate the muscarinic effects on signal processing and synaptic plasticity.

 


from: Alzheimer & Wess, Neuroforum 2/05, 2005


References:

  • Mittmann T and Alzheimer C: Muscarinic inhibition of persistent Na+ current in rat neocortical pyramidal neurons. J Neurophysiol 79: 1579-1582, 1998.
  • Seeger T and Alzheimer C: Muscarinic activation of inwardly rectifying K+ conductance reduces EPSPs in rat hippocampal CA1 pyramidal cells. J Physiol (Lond.) 535: 383-396, 2001.
  • Seeger T, Fedorova I, Zheng F, Miyakawa T, Koustova E, Gomeza J, Basile AS, Alzheimer C and Wess J. M2 muscarinic acetylcholine receptor knockout mice show deficits in behavioral flexibility, working memory, and hippocampal plasticity. J Neurosci 24:10117-10127, 2004.
  • C. Alzheimer and Wess J: Muskarinische Acetylcholin-Rezeptoren und die neuronalen Mechanismen kognitiver Leistungen. Neuroforum 2.05: 61-66, Elsevier/Spektrum Akademischer Verlag, 2005. 
  • Gautam D, Duttaroy A, Cui Y, Han SJ, Deng C, Seeger T, Alzheimer C, Wess J: M1-M3 muscarinic acetylcholine receptor-deficient mice: novel phenotypes. J Mol Neurosci 30(1-2):157-60, 2006.

IV. Biological Significance of Ion Channels in Non-Excitable Cells

How does the activity of ion channels influence proliferation and differentiation of non-excitable cells? Do extracellular signaling molecules target ion channels to exert biologically significant actions on non-excitable cells? Does the pharmacological blockade or activation of ion channels have an impact on growth and differentiation? Are altered channel expression pattern associated with diseases? We use human keratinocytes to investigate this kind of questions, employing a combination of electrophysiological and molecular biological techniques (the latter with the help of Prof. Werner, ETH Zurich).

References:

  • Koegel H and Alzheimer C: Expression and biological significance of Ca2+-activated ion channels in human keratinocytes. FASEB J 15:145-154, 2001.
  • Burgstahler R, Koegel H, Rucker F, Tracey D, Grafe P and Alzheimer C. Confocal ratiometric voltage imaging of cultured human keratinocytes reveals layer-specific responses to ATP. Am J Physiol Cell Physiol 284: C944-C952, 2003.
  • Koegel H, Kaesler S, Burgstahler R, Werner S and Alzheimer C: Unexpected down-regulation of the hIK1 Ca2+-activated K+ channel by its opener 1-EBIO in HaCaT keratinocytes: inverse effects on cell growth and proliferation. J Biol Chem 278: 3323-3330, 2003.