Prof. Volkmar Lessmann

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Team Name:
 ‘Neurophysiology, live-cell imaging, and behavioral analysis of learning and memory

Link to team page:
http://www.iphy.ovgu.de/Labore/Labor+Synaptische+Plastizit%C3%A4t.html
https://forschung-sachsen-anhalt.de/pl/lessmann-83389

Institute: Institute of Physiology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Germany

Address: Leipziger Strasse 44, Haus 13, 39120 Magdeburg, Germany

Description of research

dr-thomas-endres-team-lessmann-lab (ori)Our research is dedicated to the molecular and cellular mechanisms of synaptic plasticity and their role in learning and memory in behaving animals. Synaptic plasticity is heavily regulated by so called neuromodulatory transmitters (such as dopamine and noradrenaline) and by secreted neuropeptides such as neuropeptide Y (NPY) or brain-derived neurotrophic factor (BDNF). In recent years, our lab contributed extensively to disentangling the role of BDNF in regulating synaptic transmission. In 1994, we were the first to report that BDNF can enhance excitatory synaptic transmission in mammals. In 2001, we first visualized postsynaptic secretion of BDNF in response to synaptic stimulation. Since then, our lab was strongly involved in investigating the role that synaptic BDNF secretion plays in regulating synaptic plasticity and memory formation. To this aim, our experimental approaches cover techniques ranging from molecular biology (to generate fluorescently labeled reporter proteins like e.g. BDNF-GFP), over cellular neurobiology (electrophysiology and live cell imaging) up to bahavioral analysis.

We employ electrohysiological recordings of long-term potentiation (LTP) and spike timing-dependent plasticity (STDP) in brain tissue from rats and mice to identify cellular mechanisms that are important for memory formation. Using behavioral analysis of mice, we aim to characterize molecular signaling cascades underlying hippocampus-dependent spatial learning (Morris water maze, novel object recognition tests) and amygdala-, hippocampus- and cortex- dependent fear learning as well as fear extinction. By means of live cell imaging of fluorescently (GFP) labeled proteins in cultured neurons and isolated brain slices we follow the intracellular transport, synaptic targeting and exocytotic release of these proteins (e.g., neurotrophins) upon physiological stimulation of neuronal cells.

dr-elke-edelmann-team-lessmann-lab (ori)The protein brain-derived neurotrophic factor (BDNF) belongs to the family of neurotrophins which are secreted as neurotrophic factors into the extracellular space (other members are NGF, NT-3, and NT-4/5). Neurotrophins enhance neuronal survival, development and maintenance of synaptic functions throughout the brain during embryonic and early postnatal development. In the adult, neurotrophins play additional important roles in inducing, maintaining and regulating synaptic plasticity – a phenomenon that is generally accepted as a cellular correlate of memory formation. (BDNF) is the best investigated neurotrophin with respect to synaptic plasticity. It is stored in secretory granules (so called large dense core vesicles, LDCVs), which are released either constitutively or in an activity-dependent manner. BDNF release can take place from the soma, axons and dendrites of neurons.

Apart from BDNF, our lab has an additional strong focus on signaling of neuromodulatory transmitters (especially dopamine) in regulating long-term potentiation (LTP). We could show very recently that spike timing-dependent plasticity (STDP), a form of synaptic plasticity that can be observed upon very mild and physiologically relevant levels of synaptic stimulation, requires endogenous dopamine to be efficient. Similarly, postsynaptic secretion of endogenous BDNF from hippocampal CA1 pyramidal neurons is responsible for rhythms of STDP stimulation that depend on burst firing of action potentials in the postsynaptic neuron. Interestingly, dopamine and BDNF in fact seem to act in concert to fine tune synaptic plasticity and the mutual regulation of both neuromodulatory systems is the basis of many of our studies.

team-lessmann-lab-after-exercise (sml)BDNF and dopamine signaling are also of high relevance for learning and memory in humans. Extracellular levels of endogenous dopamine reflect our motivation for learning. Accordingly, dopamine has been identified long time ago to shape synaptic plasticity events like LTP in animal models and to enhance memory formation in humans. On the same vein, BDNF has been shown in humans and in rodents to be increased in concentration in the brain by physical exercise, while physical rest and dementia – including Alzheimer’s disease are accompanied by decreased brain BDNF levels. Since brain BDNF levels can equilibrate with BDNF content in the blood stream, the blood BDNF content is considered to read out at least in part the extracellular level of this neurotrophin in brain tissue. Using BDNF ELISA measurements of human blood samples our lab therefore investigates a possible role of BDNF as a biomarker in diverse neurological, psychiatric and neurodegenerative diseases including dementia, schizophrenia and major depression.  

Research to be done in the context of Circprot

Our preliminary data indicate that long-term potentiation (LTP) and hippocampus-dependent learning are both severely reduced in a mouse model of familial Alzheimer’s disease (APP/PS1 mice). We hypothesize that high availability of endogenous BDNF compensates the neurodegenerative processes going on during development of AD. Thus, AD becomes apparent when these BDNF compensatory processes decline. Therefore the CircProt consortium will test whether manipulations that increase endogenous brain BDNF levels can delay the outbreak of AD in our animal model. This would suggest that similar strategies could delay the outbreak and progression of AD also in humans.

We will therefore investigate whether treatment of AD mice with therapeutics and treatments that enhance brain BDNF levels slows down AD progression. To this aim we team up with several partnering labs of CircProt:

  1. Together with the lab of Helene Marie we will employ electrophysiological recordings of LTP and behavioral analysis of memory function to quantify BDNF-dependent delay of LTP decline in APP/PS1 mice.

  2. In collaboration with the lab of Kurt Gottmann we will investigate whether the reduced number of synaptic contacts (so called spines) correlates with altered memory capabilities in AD mice and whether spine numbers and also memory can be retained by increased BDNF in the brain.

  3. By virtue of computational modelling of hippocampal synaptic circuits pioneered by our collaborator Michele Migliore the Marie, Gottmann, and Lessmann labs aim at disentangling the memory deficits of APP/PS1 mice at the cellular circuit level.

  4. We will provide Eero Castren and Clive Bramham with brain tissue from treated AD mice to enable a thorough biochemical analysis of BDNF-TrkB receptor signaling that might underly the beneficial effects of endogenous BDNF in delaying memory dysfunction in APP/PS1 mice.

  5. Together with the labs of Elena Cattaneo and Frederic Saudou we will analyze the properties of neuronal BDNF secretion in patient-derived neuronal differentiated induced pluripotent stem cells (iPSCs). These studies will be helpful to pinpoint whether therapeutics can be developed that increase endogenous BDNF secretion, that might be able to delay the progression of Huntington’s disease (HD).

  6. Furthermore, our lab will perform the BDNF ELISA analysis of all APP/PS1 mouse tissue within the consortium, thus enabling the quantitative correlation of any disease related changes with BDNF content of the brain. 


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Fig.1: Immuno-histochemical staining of a mouse hippocampal brain slice. Somata of CA1 pyramidal neurons are shown in red dendritic processes are visible in blue. 


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Fig.2: MAP2 antibody staining (blue) of dendrites in cultured hippocampal neurons. The lower neuron was co-transfected with plasmids coding for BDNF-mCherry (red) and CAPS1-YPet (green)

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Fig.3: A: Mouse hippocampal brain slice. B: CA1 pyramidal neurons in a hippocampal brain slice (magnified from white box in A). C: CA1 neuron dendrite (green) with presynaptic terminals (red; magnified from white box in B). D: Postsynaptic spine (green) and neighbouring presynaptic bouton (red; magnified from white box in C)

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Fig.4: APP/PS1 mouse during treadmill exercise 

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Fig.5 GFP-labelled pyramidal neurons in the mouse hippocampus

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Fig.6: Confocal imaging at a Laser scanning microscope in the Lessmann Lab

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Fig.7: Recording BDNF-GFP secretion from hippocampal neurons in the Lessmann lab

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Fig.8: STDP and BDNF secretion a) Recording of synaptic strength (i.e. “EPSP slope”) vs. time induced by a single shock STDP protocol (blue) and a theta burst STDP pattern (red), respectively. Both types of synaptic plasticity coexist and can be induced subsequently in the same pair of synaptically connected neurons in the hippocampus. Both STDP stimulation protocols lead to different types of synaptic strengthening (LTP) in hippocampal neurons. However, theta burst STDP leads to secretion of BDNF that generates LTP, whereas the single shock LTP occurs independent of BDNF release and action. b) Hippocampal neuron containing fluorescently labelled BDNF (green) in the processes of the receiving (postsynaptic) cell. Colored regions of interest show BDNF containing vesicles which are secreted by theta burst-like stimulation (modified from Edelmann et al., Neuron, 2015)
 

Key publications

Edelmann E, Cepeda-Prado E, Franck M, Lichtenecker P, Brigadski T, Lessmann V (2015) Theta burst firing recruits BDNF release and signaling in postsynaptic CA1 neurons in spike timing-dependent LTP. Neuron 86(4):1041-54.

Meis S, Endres T, Lessmann V (2012) Postsynaptic BDNF signalling regulates long-term potentiation at thalamo-amygdala afferents. J Physiol 590: 193-208.

Kolarow R, Brigadski T, Lessmann V (2007) Postsynaptic secretion of BDNF and NT-3 from hippocampal neurons depends on calcium calmodulin kinase II signaling and proceeds via delayed fusion pore opening. J Neurosci 27:10350-10364.

Brigadski T, Hartmann M, Lessmann V (2005) Differential vesicular targeting and time course of synaptic secretion of the mammalian neurotrophins. J Neurosci 25:7601-7614.

Hartmann M, Heumann R, Lessmann V (2001) Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J 20:5887-5897.