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Project Co-ordinator:

Prof. Leszek Kaczmarek
http://neurogene.nencki.gov.pl
l.kaczmarek@nencki.gov.pl
Nencki Institute
Warsaw, POLAND

 

Project Manager:

Ms. Marta Rucinska
m.rucinska@nencki.gov.pl
Nencki Institute
Warsaw, POLAND

 

Recruitment Co-ordinator

Prof. Alexander Dityatev
alexander.dityatev@dzne.de
Deutsches Zentrum fur
Neurodegenerative Erkrankungen
Magdeburg, GERMANY

 

Training Co-ordinator

Prof. Robert Pawlak
R.Pawlak@exeter.ac.uk
University of Exeter Medical School
Exeter, UK

ESR4:    Neurotrypsin and mental retardation (lead: DZNE-2a, partners: DZNE-2b, FMI)

Maura Ferrer Ferrer

maura.ferrer@dzne.de

Maura.jpg

 

 

 

 

 

 

 

 

The neuronal serine protease neurotrypsin (NT) has been recognized to play an indispensable role in cognitive processes in humans and its deficiency results in severe mental retardation (Molinari et al., 2002). Previous studies revealed that NT is released from presynaptic terminals in its inactive form and is activated in the extracellular space by a NMDA receptor-dependent mechanism. Activated neurotrypsin cleaves extracellular matrix (ECM) protein agrin and releases a C-terminal 22 kDa fragment, which induces dendritic filopodia formation (Matsumoto-Miyai et al., 2009). This is a new and very striking function for structural ECM proteins, which thus can serve as messengers for modulation of synaptic plasticity and cognition (Senkov et al., 2014). Although growth of new dendritic filopodia accompanies some forms of synaptic plasticity and learning, the role of neurotrypsin in these processes is not yet properly defined. The aim of this study is to verify the functional importance of NT in vivo. In order to achieve this aim, we investigated how does deficiency in NT in the mouse brain can affect functional synaptic plasticity, learning-induced spine formation, emotional and object recognition memories and social behaviour. The results reveal impairments of specific forms of long-term potentiation, behaviour and spinogenesis in NT deficient mice and thus form a basis for a search of mechanistic treatments that would restore plasticity and behaviour in these mutants. This could be an important step towards development of new therapeutics of the NT-dependent form of mental retardation in humans.



This PhD fellowship is available at the Molecular Neuroplasticity Research Group in DZNE Magdeburg headed by Prof. Alexander Dityatev. The group is investigating the role of cell adhesion and extracellular matrix molecules in physiological and pathological plasticity, particularly in rodent models of dementia, epilepsy and schizophrenia, using patch clamp and multielectrode array recordings, functional imaging, optogenetics, viral, enzymatic and pharmacological manipulations in vitro and in vivo.

 

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Mechanisms of neurotrypsin-mediated spinogenesis. The neuronal serine protease neurotrypsin is stored in presynaptic nerve endings and secreted in an inactive form in association with synaptic activity (AP). Its activation requires an NMDA receptor-dependent postsynaptic process. Activated neurotrypsin cleaves agrin and yields a C-terminal 22-kDa fragment (agrin-22), which is instrumental for the formation of dendritic filopodia. From: Dityatev et al. (2010) Nat. Rev. Neurosci. 11: 735-46.


For more information about research in the group, please see recent papers and reviews:
 

  • Dityatev & Rusakov (2011) Molecular signals of plasticity at the tetrapartite synapse. Curr Opin Neurobiol. 2011, 21:353-9;
  • Caiazzo et al. (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476:224-7;
  • Dityatev et al. (2010) The dual role of the extracellular matrix in synaptic plasticity and homeostasis. Nat Rev Neurosci. 11:735-46;
  • Kochlamazashvili et al. (2010) The extracellular matrix molecule hyaluronic acid regulates hippocampal synaptic plasticity by modulating postsynaptic L-type Ca2+ channels. Neuron 67:116-28.



The German Center for Neurodegenerative Diseases (DZNE) is a center of excellence within the Helmholtz Association that performs translational research on Neurodegenerative Diseases. The DZNE Magdeburg offers an excellent infrastructure in a unique research environment, with combination of animal and clinical research and in close collaborataion with reserchers from the Leibniz Institute for Neurobiology