Applied research

Neuronal signalling pathways: Stabilization of synapses

The malfunction of genes responsible for the formation and stabilization of synapses plays an important role in the development and progression of diseases of the central nervous system. Consequently, neurodegenerative and mental disorders are associated with a change in size and the loss of excitatory and inhibitory synapses in specific areas of the brain.

We are investigating the molecular mechanisms of synapse formation and stabilization in vitro and in vivo. To this end, gene transfer methods (viral RNA interference or overexpression of mutated proteins) are combined with immunohistochemical methods. 3D reconstruction of immunostained synapses is employed to quantify synapses in tissue or cell cultures.

In inhibitory synapses, GABAA receptors are organized by means of submembrane gephyrin clusters. We investigate transmembrane receptors and neuronal signalling pathways that control the number and size of gephyrin clusters. For example, we found the cell adhesion molecule neurofascin, which is expressed on the axon initial segment, to be involved in the stabilization of gephyrin clusters in vivo. This function is regulated through the interaction with FGFR1.

Current research topics:

  • Induced pluripotent stem cells for neuronal cultures as a test system for schizophrenia (PONS)

  • Systems for drug development in the field of depression and pain (Decipher)

  • Regulation of interneuron connectivity

  • Synaptic stability in neurodegenerative diseases (Mitomodels)

  • Signal transduction of gephyrin clustering

  • GABAA receptors in posttraumatic stress disorders (P2DS)

Publications:

Saha R., Knapp S., Chakraborty D., Horovitz O., Albrecht A., Kriebel M. , Kaphzan H., Ehrlich I., Volkmer H. , G. Richter-Levin (2016). GABAergic synapses at the axon initial segment of basolateral amygdala projection neurons modulate fear extinction. Neuropsychopharmacology. Manuscript accepted for publication.

Beuter S, Ardi Z, Horovitz O, Wuchter J, Keller S, Saha R, Tripathi K, Anunu R, Kehat O, Kriebel M, Richter-Levin G, Volkmer H.
Receptor tyrosine kinase EphA7 is required for interneuron connectivity at specific subcellular compartments of granule cells. Scientific Reports 2016; 6:29710.

Zitman FM, Lucas M, Trinks S, Grosse-Ophoff L, Kriebel M, Volkmer H, Richter-Levin G.
Dentate Gyrus Local Circuit is Implicated in Learning Under Stress-a Role for Neurofascin. Mol Neurobiol.2016 Mar;53(2):842-50.

Kaistha BP, Honstein T, Muller V, Bielak S, Sauer M, Kreider R, Fassan M, Scarpa A, Schmees C, Volkmer H, Gress TM, Buchholz M. (2014).
Key role of dual specificity kinase TTK in proliferation and survival of pancreatic cancer cells.Br J Cancer. 2014 Oct 28;111(9):1780-7. doi: 10.1038/bjc.2014.460.

Fa M, Xia L, Anunu R, Kehat O, Kriebel M, Volkmer H, Richter-Levin G (2014). Stress modulation of hippocampal activity--spotlight on the dentate gyrus. Neurobiol Learn Mem 2014 Jul; 112:52-60.

Wuchter J, Beuter S, Treindl F, Herrmann T, Zeck G, Templin MF, Volkmer H (2012). A Comprehensive Small Interfering RNA Screen Identifies Signaling Pathways Required for Gephyrin Clustering. The Journal of Neuroscience, October 17, 32(42):14821–14834.

Kriebel et al.(2012). Neurofascin: a switch between neuronal plasticity and stability. Int J Biochem Cell Biol. 44(5):694-7.

Kriebel M, Metzger J, Trinks S, Chugh D, Harvey RJ, Harvey K, Volkmer H. (2011). The cell adhesion molecule neurofascin stabilizes axo-axonic GABAergic terminals at the axon initial segment. J Biol Chem. 2011 Jul 8;286(27):24385-93.

Kirschbaum K, Kranz E, Kriebel M, and Volkmer H. (2009). Analysis of non-canonical FGFR1 interaction reveals regulatory and activating domains of neurofascin. Journal of Biological Chemistry 284: 28533-28542.

Hansen RK, Christensen C, Korshunova1 I, Kriebel M, Burkarth N, Kiselyov VV, Olsen M, Østergaard S, Holm A, Volkmer H, Walmod PS, Berezin V and Bock E (2007). Identification of NCAM-binding peptides promoting neurite outgrowth via a heterotrimeric G-protein-coupled pathway. Journal of Neurochemistry 103(4):1396-407.

Burkarth N., Kriebel M., Kranz E. and Volkmer H (2007). Neurofascin regulates the formation of Gephyrin clusters and subsequent translocation to the axon hillock of hippocampal neurons. Mol Cell. Neurosci. 36(1):59-70.

Niere M, Braun B, Gass R, Sturany S and Volkmer H (2006). Combination of engineered neural cell adhesion molecules and GDF-5 for improved neurite extension in nerve guide concepts. Biomaterials 27(18):3432-40.

Pruss T, Kranz E, Niere M and Volkmer H (2006). A regulated switch of chick neurofascin isoforms modulates ligand recognition and neurite extension. Mol. Cell Neurosci. 31(2):354-65.

Pruss T, Niere M, Kranz E, and Volkmer H (2004). Homophilic interactions of neural cell adhesion molecule neurofascin are important for cell adhesion and neurite induction. Eur. J. of Neurosci. 20: 3184-3188.