Rolf Sprengel is a molecular biologist who was trained in virology and microbiology in the research units of Heinz Schaller in Heidelberg, of Harald Varmus in San Francisco and of Hans Will at the MPI for Biochemistry in Martinsried, Munich. As a senior scientist, Rolf Sprengel turned his interest to Neurobiology, and he was getting actively involved in the cloning of several neurotransmitter receptors when he joined the group of Peter Seeburg at the ZMBH in Heidelberg in spring 1988. After the cloning and the characterization of several G-protein coupled receptors, genes for GABAA, inotropic glutamate receptors (AMPA- and NMDA-receptors), kainate receptors and the discovery of site-selective pre-mRNA-editing of AMPA in Seeburgs's lab [1], Rolf Sprengel’s major interest was to generate gene-modified mouse models for the experimental analysis of the function of AMPA and NMDA receptors in learning and memory.

The close collaboration of Peter Seeburg with Bert Sakmann’s, Per Andersen’s and Nick Rawlin’s in Heidelberg, Oslo and Oxford, respectively, opened Rolf Sprengel a very unique gate to use reverse genetic approaches to unravel the function of the different AMPA- and NMDA-receptor subtypes at different levels (a single receptor on a cell, the receptor function in neuronal circuits and behavioural changes) in mice within the outstanding professional scientific environment.

Rolf Sprengel focused his research on the essential contribution of AMPA- and NMDA-receptors in memory formation and neurodegeneration. For both mechanisms NMDA receptor mediated Ca2+-influx was speculated to be the most important signalling molecule. Therefore, as group leader in Peter Seeburg’s department at the Max Planck Institute for Medical Research in Heidelberg, Rolf Sprengel and his graduate students generated genetically modified mice, which express ionotropic glutamate receptors with impaired Ca2+-permeability or altered receptor functions by gene-targeting or by traditional transgenic approaches. Using these mouse lines, Rolf Sprengel could show which mutation are 'gain of function' or 'loss of function' mutations [2, 3]. He took advantage of this knowledge for the successful development of the several conditionally regulated mouse models by using the Cre-lox and the Doxycycline-regulated system [3-7], with the advice from Klaus Rajewski and Herman Bujard, respectively. Subsequently he used this 'Know How' for the application of Doxycycline-regulated gene expression for the transient expression of viral transduced genes [8-10]. In addition, by virus mediated gene-transfer Rolf Sprengel could show, in collaboration with Markus Schwaninger (now University of Lübeck) and Stefan Wölfl (Heidelberg University), that over expression of bone morphogenic factor BMP2 reduces the brain damage after stroke in mice [11] and that rAAV mediate gene delivery can be used for monitoring neuronal activity in mice by two photon microscopy; collaboration with Winfried Denk at the MPImf and Roger Tsien from the Stanford University [12, 13].

As senior scientist in Peter Seeburg's department at the ZMBH and later as group leader in the Department of Molecular Neurobiology in the Seeburg's Department 'Molecular Neurobiology' at the Max Planck Institute for Molecular Neurobiology, Rolf Sprengel and his collaborators were able to dissect molecular key mechanisms that underlie cognition and psychological disorders by using his Rolf Sprengel's genetically modified mice; experimental findings that established new research strategies in Neuroscience:

1) Mice lacking the GluA1 containing AMPA receptors are covering all relevant aspects of mouse models for schizophrenia and depression [14-18].

2) Hippocampal NMDA-receptors are used for decision-making but not for memory storage [4].

3) The electrophysiological induced, NMDA-receptor dependent improved synaptic transmission (Long-Term Potentiation; LTP) in acute hippocampal slices is not an experimental readout for learning and memory formation [4, 19, 20].

4) Virus mediated over-expression of SHANK2 mutations in the mouse can be monitored by autism spectrum disorder (ASD) like behaviour [21].

The years after:

Research topic of the Max Planck Research Group 'Molecular Neurobiology'

After the shut down of the 'Dept. for Molecular Neurobiology' at the Max Planck Institute for Medical Research in 2013, I continued my research activity with the dream to identify useful diagnostic and therapeutic targets for the treatment of psychological and cognitive disorders by using genetically-modified mice with impaired expression of ionotropic NMDA- and AMPA-glutamate receptors and the postsynaptic organizer protein SHANK2.

As you all know, learning and memory requires a central nervous system that can adjust its focused activity according to the current situation and in an experience dependent manner. This fast and very focused flexibility of the neuronal network activity is most likely based on short- or long-term up- and down-regulation of synaptic transmission at excitatory and inhibitory synapses; a process which is very well studied at excitatory synapses called synaptic plasticity. Of central importance for the fast neurotransmission and its plasticity are the ionotropic glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the N-methyl-D-aspartate (NMDA)-receptor subtypes (for review see e.g. [22]) and receptor-associated proteins that organise the structure and the efficiency at excitatory synapses and the intracellular trafficking of the receptors (Hanley & Wilkinson Nat. Reviews (2016) Neuroscience 17, 337–350). Therefore, the mapping of many mutations in genes for AMPA- and NMDA-receptors as well as for synaptic organiser proteins (e.g. SHANK proteins) in human patients suffering from cognitive and psychological disorders (see e.g. Berkel et al. (2012) Hum. Mol. Genet. 21, 344–357; Endele et al. (2010) Nat Genet 42, 1021–1026; Burnashev & Szepetowski (2015) Curr Opin Pharmacol 20, 73–82. Rojas (2014) J Neural Transm 121, 891–905) and AMPA receptor trafficking as FRRS1l (Brechet A et al. (2017). Nat Commun 8, 1–14) were not unexpected. In particular, since all studies using my genetic-manipulated mice showed already that mutations in NMDA- and AMPA-receptors or SHANK2 genes are correlated with behavioural impairments associated with cognitive and psychological disorders – studies performed in close collaboration with my close friends David Bannerman (University of Oxford), David Sanderson (Durham University), Peter Gass and Dragos Inta (Central Institute of Mental Health in Mannheim; CIMH), Gudrun Rappold (University Heidelberg), Øivind Hvalby and Vidar Jensen (University Oslo) and also documented by other collaborations (e.g. Andrew Holmes (NIH, USA) [23]. Together, these studies provided strong evidence that mouse models can dissect molecular and component during cognition and represent very valuable animal models to study experimentally the molecular, physiological and neuronal network activity in mental disorders.

1.         Sommer, B., Kohler, M., Sprengel, R., and Seeburg, P.H. (1991) Rna Editing in Brain Controls a Determinant of Ion Flow in Glutamate-Gated Channels. Cell (67):  11-19.

2.         Brusa, R., Zimmermann, F., Koh, D.S., Feldmeyer, D., Gass, P., Seeburg, P.H., and Sprengel, R. (1995) Early-Onset Epilepsy and Postnatal Lethality Associated with an Editing-Deficient Glur-B Allele in Mice. Science (270):  1677-1680.

3.         Single, F.N., Rozov, A., Burnashev, N., Zimmermann, F., Hanley, D.F., Forrest, D., Curran, T., Jensen, V., Hvalby, O., Sprengel, R., and Seeburg, P.H. (2000) Dysfunctions in Mice by Nmda Receptor Point Mutations Nr1(N598q) and Nr1(N598r). J. Neurosci. (20):  2558-2566.

4.         Bannerman, D.M., Bus, T., Taylor, A., Sanderson, D.J., Schwarz, I., Jensen, V., Hvalby, O., Rawlins, J.N., Seeburg, P.H., and Sprengel, R. (2012) Dissecting Spatial Knowledge from Spatial Choice by Hippocampal Nmda Receptor Deletion. Nat. Neurosci. (15):  1153-1159.

5.         Krestel, H.E., Mayford, M., Seeburg, P.H., and Sprengel, R. (2001) A Gfp-Equipped Bidirectional Expression Module Well Suited for Monitoring Tetracycline-Regulated Gene Expression in Mouse. Nucleic Acids Res. (29):  E39.

6.         Krestel, H.E., Shimshek, D.R., Jensen, V., Nevian, T., Kim, J., Geng, Y., Bast, T., Depaulis, A., Schonig, K., Schwenk, F., Bujard, H., Hvalby, O., Sprengel, R., and Seeburg, P.H. (2004) A Genetic Switch for Epilepsy in Adult Mice. J. Neurosci. (24):  10568-10578.

7.         Niewoehner, B., Single, F.N., Hvalby, O., Jensen, V., Borgloh, S.M., Seeburg, P.H., Rawlins, J.N., Sprengel, R., and Bannerman, D.M. (2007) Impaired Spatial Working Memory but Spared Spatial Reference Memory Following Functional Loss of Nmda Receptors in the Dentate Gyrus. Eur. J. Neurosci. (25):  837-846.

8.         Chen, Y., Cao, L., Luo, C., Ditzel, D.A., Peter, J., and Sprengel, R. (2013) Range: Gene Transfer of Reversibly Controlled Polycistronic Genes. Mol Ther Nucleic Acids (2):  e85.

9.         Dogbevia, G.K., Marticorena-Alvarez, R., Bausen, M., Sprengel, R., and Hasan, M.T. (2015) Inducible and Combinatorial Gene Manipulation in Mouse Brain. Front. Cell. Neurosci. (9):  142.

10.       Dogbevia, G.K., Robetamanith, M., Sprengel, R., and Hasan, M.T. (2016) Flexible, Aav-Equipped Genetic Modules for Inducible Control of Gene Expression in Mammalian Brain. Mol Ther Nucleic Acids (5):  e309.

11.       Heinonen, A.M., Rahman, M., Dogbevia, G., Jakobi, H., Wolfl, S., Sprengel, R., and Schwaninger, M. (2014) Neuroprotection by Raav-Mediated Gene Transfer of Bone Morphogenic Protein 7. BMC Neurosci. (15):  38.

12.       Lissek, T., Obenhaus, H.A., Ditzel, D.A., Nagai, T., Miyawaki, A., Sprengel, R., and Hasan, M.T. (2016) General Anesthetic Conditions Induce Network Synchrony and Disrupt Sensory Processing in the Cortex. Front. Cell. Neurosci. (10):  64.

13.       Wallace, D., Zum Alten Borgloh, S., Astori, S., Yang, Y., Bausen, M., Kügler, S., Palmer, A., Tsien, R., Sprengel, R., Kerr, J., Denk, W., and Hasan, M. (2008) Single-Spike Detection in Vitro and in Vivo with a Genetic Ca2+ Sensor. Nat Meth (5):  797-804.

14.       Barkus, C., Feyder, M., Graybeal, C., Wright, T., Wiedholz, L., Izquierdo, A., Kiselycznyk, C., Schmitt, W., Sanderson, D.J., Rawlins, J.N., Saksida, L.M., Bussey, T.J., Sprengel, R., Bannerman, D., and Holmes, A. (2012) Do Glua1 Knockout Mice Exhibit Behavioral Abnormalities Relevant to the Negative or Cognitive Symptoms of Schizophrenia and Schizoaffective Disorder? Neuropharmacology (62):  1263-1272.

15.       Fitzgerald, P.J., Barkus, C., Feyder, M., Wiedholz, L.M., Chen, Y.C., Karlsson, R.M., Machado-Vieira, R., Graybeal, C., Sharp, T., Zarate, C., Harvey-White, J., Du, J., Sprengel, R., Gass, P., Bannerman, D., and Holmes, A. (2010) Does Gene Deletion of Ampa Glua1 Phenocopy Features of Schizoaffective Disorder? Neurobiol. Dis. (40):  608-621.

16.       Inta, D., Monyer, H., Sprengel, R., Meyer-Lindenberg, A., and Gass, P. (2010) Mice with Genetically Altered Glutamate Receptors as Models of Schizophrenia: A Comprehensive Review. Neurosci. Biobehav. Rev. (34):  285-294.

17.       Sanderson, D.J., Good, M.A., Seeburg, P.H., Sprengel, R., Rawlins, J.N., and Bannerman, D.M. (2008) The Role of the Glur-a (Glur1) Ampa Receptor Subunit in Learning and Memory. Prog. Brain Res. (169):  159-178.

18.       Wiedholz, L.M., Owens, W.A., Horton, R.E., Feyder, M., Karlsson, R.M., Hefner, K., Sprengel, R., Celikel, T., Daws, L.C., and Holmes, A. (2008) Mice Lacking the Ampa Glur1 Receptor Exhibit Striatal Hyperdopaminergia and 'Schizophrenia-Related' Behaviors. Mol. Psychiatry (13):  631-640.

19.       Shimshek, D.R., Jensen, V., Celikel, T., Geng, Y., Schupp, B., Bus, T., Mack, V., Marx, V., Hvalby, O., Seeburg, P.H., and Sprengel, R. (2006) Forebrain-Specific Glutamate Receptor B Deletion Impairs Spatial Memory but Not Hippocampal Field Long-Term Potentiation. J. Neurosci. (26):  8428-8440.

20.       Zamanillo, D., Sprengel, R., Hvalby, O., Jensen, V., Burnashev, N., Rozov, A., Kaiser, K.M., Koster, H.J., Borchardt, T., Worley, P., Lubke, J., Frotscher, M., Kelly, P.H., Sommer, B., Andersen, P., Seeburg, P.H., and Sakmann, B. (1999) Importance of Ampa Receptors for Hippocampal Synaptic Plasticity but Not for Spatial Learning. Science (284):  1805-1811.

21.       Berkel, S., Marshall, C.R., Weiss, B., Howe, J., Roeth, R., Moog, U., Endris, V., Roberts, W., Szatmari, P., Pinto, D., Bonin, M., Riess, A., Engels, H., Sprengel, R., Scherer, S.W., and Rappold, G.A. (2010) Mutations in the Shank2 Synaptic Scaffolding Gene in Autism Spectrum Disorder and Mental Retardation. Nat. Genet. (42):  489-491.

22.       Sprengel, R., Ionotropic Glutamate Receptors, in Neuroscience in the 21st Century - from Basic to Clinical, D.W. Pfaff, Editor. 2013, Springer: Ney York. p. 59-80.

23.       Kiselycznyk, C., Jury, N.J., Halladay, L.R., Nakazawa, K., Mishina, M., Sprengel, R., Grant, S.G., Svenningsson, P., and Holmes, A. (2015) Nmda Receptor Subunits and Associated Signaling Molecules Mediating Antidepressant-Related Effects of Nmda-Glun2b Antagonism. Behav. Brain Res. (287):  89-95.

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