Contact

Sprengel, Rolf
Rolf Sprengel
Phone: +49 6221 54 86 68
Fax: +49 6221 486-163

References

1.
Sanderson, D. J.; Gray, A.; Simon, A.; Taylor, A. M.; Deacon, R. M. J.; Seeburg, P. H.; Sprengel, R.; Good, M. A.; Rawlins, J. N. P.; Bannerman, D. M.
Deletion of glutamate receptor-A (GluR-A) AMPA receptor subunits impairs one-trial spatial memory
2.
Humeau, Y.; Reisel, D.; Johnson, A. W.; Borchardt, T.; Jensen, V.; Gebhardt, C.; Bosch, V.; Gass, P.; Bannermann, D. M.; Good, M. A.; Hvalby, Ø.; Sprengel, R.; Läthi, A.
A Pathway-Specific Function for Different AMPA Receptor Subunits in Amygdala Long-Term Potentiation and Fear Conditioning
3.
Engblom, D.; Bilbao, A.; Sanchis-Segura, C.; Dahan, L.; Perreau-Lenz, S.; Balland, B.; Parkitna, J. R.; Luján, R.; Halbout, B.; Mameli, M.; Parlato, R.; Sprengel, R.; Lüscher, C.; Schütz, G.; Spanagel, R.
Glutamate Receptors on Dopamine Neurons Control the Persistence of Cocaine Seeking
4.
Mansuy, I. M.; Winder, D. G.; Moallem, T. M.; Osman, M.; Mayford, M.; Hawkins, R. D.; Kandel, E. R.
Inducible and Reversible Gene Expression with the rtTA System for the Study of Memory
5.
Reijmers, L. G.; Perkins, B. L.; Matsuo, N.; Mayford, M.
Localization of a Stable Neural Correlate of Associative Memory
6.
Mack, V.; Burnashev, N.; Kaiser, K. M. M.; Rozov, A.; Jensen, V.; Hvalby, Ø.; Seeburg, P. H.; Sakmann, B.; Sprengel, R.
Conditional Restoration of Hippocampal Synaptic Potentiation in GluR-A-Deficient Mice
7.
Zhu, P. H.; Aller, M. I.; Baron, U.; Cambridge, S. B.; Bausen, M.; Herb, J.; Sawinski, J.; Cetin, A.; Osten, P.; Nelson, M. L.; Kügler, S.; Seeburg, P. H.; Sprengel, R.; Hasan, M. T.
Silencing and un-silencing of tetracycline-controlled genes in neurons
8.
Tang, W.; Ehrlich, I.; Wolff, S. B. E.; Michalski, A.-M.; Wölfl, S.; Hasan, M. T.; Lüthi, A.; Sprengel, R.
Faithful expression of multiple proteins via 2A-peptide self-processing: A versatile and reliable method for manipulating brain circuits
9.
Osten, P.; Grinevich, V.; Cetin, A.
Viral vectors: a wide range of choices and high levels of service
10.
Haydon-Wallace, D. J.; Meyer zum Alten Borgloh, S.; Astori, S.; Yang, Y.; Bausen, M.; Kügler, S.; Palmer, A. E.; Tsien, R. Y.; Sprengel, R.; Kerr, J.; Denk, W.; Hasan, M. T.
Single-spike detection in vitro and in vivo with a genetic Ca2+ sensor
11.
Hartmann, B.; Ahmadi, S.; Heppenstall, P. A.; Lewin, G. R.; Schott, C.; Borchardt, T.; Seeburg, P. H.; Zeilhofer, H. U.; Sprengel, R.; Kuner, R.
The AMPA Receptor Subunits GluR-A and GluR-B Reciprocally Modulate Spinal Synaptic Plasticity and Inflammatory Pain

Rolf Sprengel Group

Rolf Sprengel Group

The textbook knowledge "AMPA receptors are just essential for the fast excitatory neurotransmission" was revolutionized by our gene targeted mice deficient for AMPA receptors containing the GluRA1 subunit.

The very detailed behavioral and physiological analyses of our mice with altered GluA1 expression revealed, for the first time, that AMPA receptor plasticity is also critically involved in hippocampus-based learning and memory, thus illuminating the endogenous regulation of AMPA receptors. Several studies from us and our collaborators showed, with no doubt, that AMPA receptors with the GluA1 subunit are not essential for spatial reference memory - the gold standard for spatial learning -, but are critically involved in behavioral tasks for the spatial working memory; a learning deficiency which we could correlate with lack of some forms of long-term potentiation at CA3-to-CA1 hippocampal connections (for review see: Sanderson et al., 2007).

Besides the deficiency in spatial working memory, we could show that also in some other learning paradigms relying on amygdala and thalamus the GluA1 subunit is needed for proper operation of the respective brain regions (Humeau et al., 2007, Engblom et al., 2008). As shown in collaboration with Dr. Rohini Kuner, GluA1 receptor-mediated plasticity modulates inflammatory pain as well (Hartmann et al 2004).  Currently and in the next few years this traditional research program is continued, as can be noticed from the different funding resources of my group.

However, in order to shift the analysis of all our different mouse models with altered AMPA receptor expression to a new level, we need to establish and develop technologies which permit (a) a fast and reversible gene regulation and (b) an optical analysis of neuronal activity in the behaving mouse with long-term recording of population activity in the brain of mice or rats. First, the reversible gene regulation should allow us to monitor the function of the controlled gene in learning behavior when the gene is in the "ON" or "OFF" state in the very same mouse. Second, the simultaneous optical recording of neurons will reveal the ongoing changes in neuronal activity during and after learning in our different mouse mutants.

Both goals are tremendously challenging. But our experience over the last years and the infrastructure of the Max Planck Institute of Medical Research will support this endeavor.

The successful achievement of both goals is absolutely necessary for the molecular understanding of specific neuronal circuits in complex brain functions.

Reversible gene-regulation

There are a few pioneering studies from us an others, demonstrating that the doxycycline-controlled reversible gene regulation can be used in behavioral research (Mansuy et al., 1998, Reijmers et al., 2007, Mack et al., 2001). Yet, the epigenetic silencing of the doxycycline-controlled gene was a major difficulty with the current technology (Zhu et al., 2007). Recently, we showed a faithful, efficient co-expression of several proteins in neurons (Tang et al., 2009).

This possibility of efficient, multiple gene transfer opens attractive options to get around the silencing problem of transcriptionally inactive genes and permits the combination of several regulatory genes for fast reversible gene expression. The co-expression of counteractive doxycycline-regulated activators and silencers will be, therefore, investigated in great detail.

For the fast analysis of the different approaches, the rAAV technology is the best tool, since several transduced gene cassettes can be tested side by side in primary cultures, organotypic cultures and, finally, in the mouse (for review see Osten et al., 2007).

Monitoring the neuronal activity


<p>Activity maps of neurons in the brain of the mouse will record activity changes of functional circuits during behaviour.</p>
Zoom Image

Activity maps of neurons in the brain of the mouse will record activity changes of functional circuits during behaviour.

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In collaboration with Dr. Mazahir Hasan from our Department (see report by Dr. Mazahir Hasan) we have access to the world’s leading technology of optogentic tools, and we feel confident that optical analysis in behaving mice will be possible in the near future, as indicated by the studies of Haydon-Wallace et al., 2008, using one of the many and novel fluorescent Ca2+ indicator proteins.

AMPA receptor regulators

In addition to our conditional mouse models for AMPA and NMDA receptor 'knockouts' we will investigate a series of new endogenous proteins regulating AMPA receptor transmission. Besides the TARPs, new proteins with a strong effect on the function of the AMPA receptor complex appear on the horizon. In particular, the reversible over-expression or inactivation of these AMPAR regulating proteins during learning tasks will be investigated together with changes of neuronal activity and learning behavoiur.

We hope that our future work will provide novel insights into the function of AMPA receptors in specific neuronal circuits during learning together with solid, new methodology useful for the analysis of genes in neuronal circuit activity during higher brain functions. Needless to say that our knowledge of anatomical and physiological studies will assists our efforts, and that the contribution of motivated students of the Universities of Heidelberg and Mannheim play a active part in this adventure.

If sufficient resources are provided by the Max Planck Institute for Medical Research, we will include gene manipulation in rat ES cells and new approaches for gene targeting, using Zink-finger proteins, in our research projects.

 
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