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Molecular Dynamics of periSynaptic Extracellular Matrix

PI: Renato Frischknecht

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Issue

Learning and memory formation entails changes in information flow and processing within brain circuits. These functional changes are driven by activity-dependent structural plasticity. While structural plasticity is high in the young developing brain, it is much less evident in adulthood, where stable neuronal circuits are required for persistent memory storage. Thus, the adult brain must maintain a delicate balance between structural plasticity and tenacity to allow for learning and to protect live long memory. Recent discoveries highlight the central role of the extracellular matrix (ECM) of the brain in this process. In our research we want to understand how the ECM regulates learning, memory formation and synaptic plasticity on the systemic, cellular and molecular level. Further we investigate to what degree altered ECM turnover contributes to reduced brain plasticity and memory loss during aging.

Focus

The brain comprises a specialized form of extracellular matrix (ECM), a complex meshwork of proteoglycans and glycoproteins that emerges during adolescence. This specialized ECM has been identified as a major factor suppressing structural plasticity and supporting stability of neuronal networks in the mature brain. However, how is learning and structural plasticity achieved in the mature brain in presence of the ECM? We hypothesize that specific and local degradation of the ECM is necessary for experience-driven reorganisation of brain circuitry during learning. Subsequent replenishment of the ECM by protein synthesis and secretion stabilizes newly established neuronal networks to protect acquired memories. Following this idea, we are investigating cellular and molecular mechanisms involved in activity-dependent regulation of the ECM, their impact on synaptic transmission, synaptic plasticity and structural changes leading to network rearrangements. Further, we aim to unravel ECM-derived signalling mechanisms supporting or conversely, reducing synaptic plasticity. Finally, we are testing whether manipulation of the ECM supports learning and memory functions. Together, we hope to better understand how the balance between plasticity and stability is maintained in the brain. A balance that is necessary for efficient brain function and is dysregulated in several mental disorders such as post-traumatic stress disorder, schizophrenia and dementia.

Methods

In our research we apply molecular biological, biochemical and cell biological approaches. We have expertise in super-resolution microscopy and live-cell imaging in cultured primary neurons and brain slices. In collaboration, we perform several learning paradigms and apply electrophysiological methods.

Selected Publications

Mitlohner, J., Kaushik, R., Niekisch, H., Blondiaux, A., Gee, C.E., Happel, M.F.K., Gundelfinger, E., Dityatev, A., Frischknecht, R. & Seidenbecher, C. (2020) Dopamine Receptor Activation Modulates the Integrity of the Perisynaptic Extracellular Matrix at Excitatory Synapses. Cells, 9.

Niekisch, H., Steinhardt, J., Berghauser, J., Bertazzoni, S., Kaschinski, E., Kasper, J., Kisse, M., Mitlohner, J., Singh, J.B., Weber, J., Frischknecht, R. & Happel, M.F.K. (2019) Learning Induces Transient Upregulation of Brevican in the Auditory Cortex during Consolidation of Long-Term Memories. J Neurosci, 39, 7049-7060.

Pandya, N.J., Seeger, C., Babai, N., Gonzalez-Lozano, M.A., Mack, V., Lodder, J.C., Gouwenberg, Y., Mansvelder, H.D., Danielson, U.H., Li, K.W., Heine, M., Spijker, S., Frischknecht, R. & Smit, A.B. (2018) Noelin1 Affects Lateral Mobility of Synaptic AMPA Receptors. Cell Rep, 24, 1218-1230.

Schweitzer, B., Singh, J., Fejtova, A., Groc, L., Heine, M. & Frischknecht, R. (2017) Hyaluronic acid based extracellular matrix regulates surface expression of GluN2B containing NMDA receptors. Sci Rep, 7, 10991.

Ivanova, D., Dirks, A., Montenegro-Venegas, C., Schone, C., Altrock, W.D., Marini, C., Frischknecht, R., Schanze, D., Zenker, M., Gundelfinger, E.D. & Fejtova, A. (2015) Synaptic activity controls localization and function of CtBP1 via binding to Bassoon and Piccolo. EMBO J, 34, 1056-1077.

Bikbaev, A., Frischknecht, R. & Heine, M. (2015) Brain extracellular matrix retains connectivity in neuronal networks. Sci Rep, 5, 14527.

Blosa, M., Sonntag, M., Jager, C., Weigel, S., Seeger, J., Frischknecht, R., Seidenbecher, C.I., Matthews, R.T., Arendt, T., Rubsamen, R. & Morawski, M. (2015) The extracellular matrix molecule brevican is an integral component of the machinery mediating fast synaptic transmission at the calyx of Held. J Physiol, 593, 4341-4360.

Happel, M.F., Niekisch, H., Castiblanco Rivera, L.L., Ohl, F.W., Deliano, M. & Frischknecht, R. (2014) Enhanced cognitive flexibility in reversal learning induced by removal of the extracellular matrix in auditory cortex. Proc Natl Acad Sci U S A, 111, 2800-2805.

Valenzuela, J.C., Heise, C., Franken, G., Singh, J., Schweitzer, B., Seidenbecher, C.I. & Frischknecht, R. (2014) Hyaluronan-based extracellular matrix under conditions of homeostatic plasticity. Philos Trans R Soc Lond B Biol Sci, 369, 20130606.

Klueva, J., Gundelfinger, E.D., Frischknecht, R.R. & Heine, M. (2014) Intracellular Ca(2)(+) and not the extracellular matrix determines surface dynamics of AMPA-type glutamate receptors on aspiny neurons. Philos Trans R Soc Lond B Biol Sci, 369, 20130605.

Sakry, D., Neitz, A., Singh, J., Frischknecht, R., Marongiu, D., Biname, F., Perera, S.S., Endres, K., Lutz, B., Radyushkin, K., Trotter, J. & Mittmann, T. (2014) Oligodendrocyte precursor cells modulate the neuronal network by activity-dependent ectodomain cleavage of glial NG2. PLoS biology, 12, e1001993.

Frischknecht, R. & Seidenbecher, C.I. (2012) Brevican: A key proteoglycan in the perisynaptic extracellular matrix of the brain. Int J Biochem Cell Biol.

Frischknecht, R., Heine, M., Perrais, D., Seidenbecher, C.I., Choquet, D. & Gundelfinger, E.D. (2009) Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity. Nat Neurosci, 12, 897-904.

Frischknecht, R., Fejtova, A., Viesti, M., Stephan, A. & Sonderegger, P. (2008) Activity-induced synaptic capture and exocytosis of the neuronal serine protease neurotrypsin. J Neurosci, 28, 1568-1579.

Heine, M., Groc, L., Frischknecht, R., Beique, J.C., Lounis, B., Rumbaugh, G., Huganir, R.L., Cognet, L. & Choquet, D. (2008) Surface mobility of postsynaptic AMPARs tunes synaptic transmission. Science, 320, 201-205.

Konecna, A., Frischknecht, R., Kinter, J., Ludwig, A., Steuble, M., Meskenaite, V., Indermuhle, M., Engel, M., Cen, C., Mateos, J.M., Streit, P. & Sonderegger, P. (2006) Calsyntenin-1 docks vesicular cargo to kinesin-1. Mol Biol Cell, 17, 3651-3663.