INSTITUTE OF PHYSIOLOGY

Research

The research which is being conducted in our group can be subdivided into two general fields:

a) Neurotrophin release and synaptic plasticity b) Synaptic development in CNS neurons

Neurotrophins (NGF, BDNF, NT-3, NT-4) are a family of secreted neuronal proteins that - via binding to specialized cell surface receptors (Trks, p75) - enhance the survival and the differentiation of nerve cells. In addition, they have turned out to enhance the efficiency of synaptic contacts between neurons. Exciting new results suggest a possible therapeutic potential for neurotrophins in treating neurodegenerative diseases like e.g. Morbus Alzheimer, Morbus Huntington, and Morbus Parkinson.

JoGu-paper (Juli 2005)

 

Neurotrophin release and synaptic plasticity

 

presynklActivity-dependent changes in the efficacy of synaptic transmission, such as long-term potentiation (LTP), are considered to be the cellular correlate of learning and memory formation in the mammalian brain. The protein brain-derived neurotrophic factor (BDNF) has been postulated to be released synaptically by an activity dependent mechanism, thereby inducing synaptic modifications leading to LTP. Exogenous BDNF can indeed enhance glutamatergic synapses by means of enhancing transmitter release.

(from: Lessmann & Heumann 1998)

 

bdnfklWe are investigating the mechanism by which neurotrophins modulate synaptic transmission. Video time lapse recordings of the release of neurotrophin-GFP (green fluorescent protein) fusion proteins are helping us to understand the exact subcellular localization of neurotrophins and the necessary stimuli for neurotrophin action at central synapses.

(from: Hartmann et al., 2001)

 

Related publications:

  • I. Abidin, T. Köhler, E. Weiler, G. Zoidl, U. Eysel, V. Lessmann, T. Mittmann. Reduced presynaptic efficiency of excitatory synaptic transmission impairs LTP in the visual cortex of BDNF heterozygous mice. European Journal of Neuroscience 24:3519-3531 (2006).
  • C. Walz, K.Jungling, V. Lessmann, K. Gottmann. Presynaptic Plasticity in an Immature Neocortical Network Requires NMDA Receptor Activation and BDNF Release. Journal of Neurophysiology 96(6): 3512-3516 (2006).
  • T. Brigadski, M. Hartmann and V. Lessmann. Differential vesicular targeting and time course of synaptic secretion of the mammalian neurotrophins. Journal of Neuroscience 25(33): 7601-7614 (2005).
  • L. Gauthier, B. Charrin,M. Borrell-Pagès, F. Cordelières, J. De Mey, M. MacDonald, V. Lessmann, S. Humbert, F. Saudou. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118:127-138 (2004).
  • M. Malcangio and V. Lessmann. "Common thread for pain and memory synapses ?: Brain-derived neurotrophic factor and trkB receptors. Trends in Pharmacological Sciences 24(3): 116-121 (2003).
  • V. Lessmann, K. Gottmann and M. Malcangio. Neurotrophin secretion: present facts and future prospects. Progress in Neurobiology 69(5): 341-374 (2003).
  • M. Hartmann, R. Heumann, and V. Lessmann. Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J. 20(21),5887-97 (2001).
  • J. Paul, K. Gottmann and V. Lessmann. NT-3 regulates BDNF-induced modulation of synaptic transmission in cultured hippocampal neurons. NeuroReport 12(12):2635-9 (2001).
  • V. Leßmann. Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS. [Review]. General Pharmacology 31(5): 667-674 (1998).
  • V. Leßmann & R. Heumann. Modulation of unitary glutamatergic synapses by Neurotrophin-4/5 or Brain-derived neurotrophic factor in hippocampal microcultures: Presynaptic enhancement depends on pre-established paired-pulse facilitation. Neuroscience 86, 399-413, (1998).
  • V. Leßmann, K. Gottmann & R. Heumann. BDNF and NT-4/5 enhance glutamatergic synaptic transmission in cultured hippocampal neurons. NeuroReport 6(1), 21-25, (1994).

 

Synaptic development in CNS neurons

synapkl

currkl

 

Brain-derived neurotrophic factor (BDNF) acutely modulates the efficacy of central glutamatergic synapses via activation of the receptor tyrosine kinase TrkB. On a longer time scale, recent evidence suggests an additional role of TrkB signaling in the formation of excitatory synaptic connections.

(from: Klau et al., 2001)

 By applying e.g. electrophysiological recordings and live synaptic staining with FM styryl dyes, our group investigates the effect of neurotrophins and their receptors on the maturation of central synapses.

(from: Klau et al., 2001)

t1_filosklThe expression ratio of so-called truncated versus full-length TrkB receptors for BDNF regulates the development of dendriticfilopodia and synaptic spines.

(from: Hartmann et al., 2004)

 

 

Related publications:

  • K. Jungling, V. Eulenburg, R. Moore, R. Kemler, V. Lessmann, K. Gottmann. N-cadherin tran ssynaptically regulates short-term plasticity at glutamatergic synapses in embryonic stem cell-derived neurons. Journal of Neuroscience 26(26):6968-78.(2006).
  • M. Hartmann, T. Brigadski, K. Erdmann, B. Holtmann, M. Sendtner, F. Narz, and V. Lessmann. Truncated TrkB.T1 receptor induced outgrowth of dendritic filopodia in hippocampal neurons involves the p75 neurotrophin receptor. Journal of Cell Science 117(24): 5803-5814 (2004).
  • R. Mohrmann, V. Lessmann and K. Gottmann. Developmental maturation of synaptic vesicle cycling as a distinctive feature of central glutamatergic synapses. Neuroscience 117(1):7-18 (2003).
  • M. Klau, M. Hartmann, K. Erdmann, R. Heumann, and V. Lessmann. Reduced number of functional glutamatergic synapses in hippocampal neurons overexpressing full-length TrkB receptors. Journal of Neuroscience Research 66(3), 327-36 (2001).
  • J. Paul, K. Gottmann and V. Lessmann. NT-3 regulates BDNF-induced modulation of synaptic transmission in cultured hippocampal neurons. NeuroReport 12(12):2635-9 (2001).
  • V. Leßmann and R. Heumann. Cyclic AMP endogenously enhances synaptic strength of developing glutamatergic synapses in serum-free microcultures of rat hippocampal neurons. Brain Research 763, 111-122, (1997).

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