TU Braunschweig
Zoological Institute
Cellular Neurobiology
Biocenter
Spielmannstr. 7
38106 Braunschweig
Germany
Tel.: +49 (0)531 391 3225
Email: m.zagrebelsky[at]tu-braunschweig.de
Activity-dependent changes in the strength and structure of synaptic connections (plasticity) are the underlying mechanism by which new information is stored in the brain. On the other hand, the mature neuronal circuitry is characterized by a high degree of stability providing the correlate for long-term storage of information. Thus, learning and memory processes depend upon a tightly regulated balance between the plasticity and the stability of the neuronal circuitry. This observation indicates the requirement for different molecular cues working in an opposite and highly coordinated manner. In our research we combine molecular, imaging, neuroanatomical and electrophysiological methods to address this complex set of molecular and cellular mechanisms in the mouse hippocampus as well as their consequences for hippocampus-dependent spatial learning and memory processes both in the healthy brain and under pathological conditions.
A. Organotypic slice cultures used for structural analysis of CA3 pyramidal hippocampal neurons upon single cell electroporation of membrane-bound fluorescent proteins and for patch clamp recordings. B. Patch clamp recording traces of mEPSCs.
1.) Nogo-A has been shown to restrict both functional and structural plasticity in the mature brain. Using both in vitro and in vivo approaches we analyze the cellular and molecular mechanisms underlying its activity. Specifically, we study the ability of Nogo-A to regulate the dynamics of the actin cytoskeleton to control structural plasticity at dendritic spines at a fast time scale. Moreover, we use single particle tracing methods to analyze the role of Nogo-A in modulating receptor trafficking at synapses and thus synaptic strength. Finally, we use several behavioral approaches to assess the role of Nogo-A in regulating learning and memory processes.
A. Dendritic stretches co-expressing mCherry to label the structure and eGFP tagged actin to analyze structural plasticity and actin dynamics of dendritic spines. B. and C. Fluorescence recovery after photobleaching for eGFP-actin and analysis of the recovery curve allow the description of actin dynamics within single dendritic spines.
2.) Brain derived neurotrophic factor (BDNF) signaling via its receptor TrkB is required for structural and functional plasticity. Moreover, aberrant BDNF/TrkB levels are associated with disorders including neurodevelopmental and neurodegenerative diseases suggesting its potential relevance in their therapy. We use in vitro and in vitro approaches to test drugs acting on the endogenous signaling pathways to either modulate the levels of endogenous BDNF (Fingolimod) or to activate TrkB receptor signaling (TrkB agonist antibodies). Our first aim is to analyze their effect in promoting neuronal plasticity and learning under physiological conditions. Moreover, we test the possibility of rescuing the neuronal phenotypes observed in one prototypical neurodevelopmental disorder, Rett syndrome and one neurodegenerative disorder, Alzheimer disease.
A. Genetically encoded Ca2+ indicators allow the indirect analysis of neuronal activity in primary hippocampal neurons. B. Combining Quantum dots for single particle imaging of surface dynamics and calcium imaging allows to assess the role of calcium dynamics in receptor diffusion.
3.) Alzheimer disease is characterized by extracellular accumulation of amyloid β (Aβ) peptides and synaptic pathology accompanying the progressive cognitive impairment. Application of soluble Aβ peptides impairs long-term potentiation (LTP), strengthens long-term depression (LTD), and induces a significant loss of synapses and dendritic spines in the hippocampus. The p75NTR neurotrophin receptor specifically binds Aβ and has been shown to modulate both the plasticity and the structure of neurons under physiological conditions. Here we analyze, both in vitro and in vivo whether and by which mechanisms p75NTR might be involved in mediating the Aβ-induced negative effects on synaptic function and structure during the early phases of Alzheimer’s disease.
A. Morris water maze is used for testing hippocampus-dependent learning and memory processes. B. Learning over the training days is shown by a decrease in the latency to reach the platform as well as a switch between rand search to hippocampus-dependent direct search.