Molecular Neurobiology

Molecular Neurobiology

Research Group Leader: Rolf Sprengel

The ultimate goal of my research group for the next two years is the identification of useful diagnostic and therapeutic targets for the treatment of psychological and cognitive disorders using our genetically modified mice with impaired expression of ionotropic NMDA- and AMPA-glutamate receptors and the postsynaptic organiser protein SHANK2, which earlier studies by the Seeburg consortium e.g. [1] and others have shown to be crucial in learning and memory, i.e. in the plasticity of the central nervous system. Major findings from this earlier work of my group were that (A) mice lacking the GluA1 containing AMPAR are crucial models for schizophrenia and depression [2-6], (B) hippocampal NMDARs are used for decision-making but not for memory storage [7], (C) the electrophysiological induced, NMDAR dependent improved synaptic transmission (Long-Term Potentiation; LTP) in acute hippocampal slices is not an experimental readout for learning and memory [7-9] and (D) virus mediated over-expression of SHANK2 mutations in the mouse can be monitored by autism spectrum disorder (ASD) like behaviour [10].

[1]  Bannerman DM, Sprengel R, Sanderson DJ, McHugh SB, Rawlins JN, Monyer H, and Seeburg PH (2014). Hippocampal synaptic plasticity, spatial memory and anxiety. Nat Rev Neurosci 15, 181-192.

[2]  Bannerman DM, Bus T, Taylor A, Sanderson DJ, Schwarz I, Jensen V, Hvalby O, Rawlins JN, Seeburg PH, and Sprengel R (2012). Dissecting spatial knowledge from spatial choice by hippocampal NMDA receptor deletion. Nat Neurosci 15, 1153-1159.

[3]  Barkus C, Feyder M, Graybeal C, Wright T, Wiedholz L, Izquierdo A, Kiselycznyk C, Schmitt W, Sanderson DJ, Rawlins JN, Saksida LM, Bussey TJ, 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.

[4]  Berkel S, Tang W, Trevino M, Vogt M, Obenhaus HA, Gass P, Scherer SW, Sprengel R, Schratt G, and Rappold GA (2012). Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology. Hum Mol Genet 21, 344-357.

[5]  Fitzgerald PJ, Barkus C, Feyder M, Wiedholz LM, Chen YC, Karlsson RM, 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.

[6]  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.

[7]  Sanderson DJ, Good MA, Seeburg PH, Sprengel R, Rawlins JN, and Bannerman DM (2008). The role of the GluR-A (GluR1) AMPA receptor subunit in learning and memory. Prog Brain Res 169, 159-178.

[8]  Shimshek DR, Jensen V, Celikel T, Geng Y, Schupp B, Bus T, Mack V, Marx V, Hvalby O, Seeburg PH, 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.

[9]  Zamanillo D, Sprengel R, Hvalby O, Jensen V, Burnashev N, Rozov A, Kaiser KM, Koster HJ, Borchardt T, Worley P, Lubke J, Frotscher M, Kelly PH, Sommer B, Andersen P, Seeburg PH, and Sakmann B (1999). Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284, 1805-1811.

[10] Berkel S, Tang W, Trevino M, Vogt M, Obenhaus HA, Gass P, Scherer SW, Sprengel R, Schratt G, and Rappold GA (2012). Inherited and de novo SHANK2 variants

Research projects (2013 –present):

My group is focusing on three topics now, after physically moving from the Max Planck Institute for Medical Research to the Institute for Anatomy and Cell Biology at the Heidelberg University in 2014.

Find information on former research projects within the vita of the group leader. (Vita)

1) Schizophrenia and cognitive disorders:  To define the cellular basis and network impairments for short-term memory impairments of GluA1 deficient mice, we generated and published several conditional mouse lines with cell-type and brain region specific GluA1 gene knock-out or (Cre/lox) or Doxycycline-regulated transgenic or rAAV-mediated GluA1 expression. [1-7]. All of our studies suggest that for operative spatial working memory the communication between the hippocampus and other brain regions is necessary. Furthermore, our previous finding, that GluA1 deficient mice represent an animal model for schizophrenic disorders, could be solidified in two further studies [8, 9]. In addition, we observed and described psychological phenotype alterations in cell-type specific NMDAR knock-out mice or NMDAR subtype pharmacological inhibited mice [9, 10]. In two reviews we discussed our view of the role of the NMDAR in the hippocampus [11, 12]. In the study of Shimshek et al. we provide further evidence that hippocampal LTP is not correlated with spatial memory formation [13].

In collaboration with Dennis Kätzel (University of Ulm) we will now use GluA1 deficient mice for the detailed analysis of the prefrontal-hippocampal excitatory and inhibitory balance and the theta-frequency hippocampal-prefrontal coherence pattern - a coherence pattern postulated to be an important feature for the memory consolidation. In addition, conditional NMDAR knock-out mice will be analysed at the CIMH to dissect the role of glutamatergic mechanism and inhibitory versus excitatory neurons in mouse models for schizophrenia e.g. ‘FRRS1l’ knock-out mice that exhibit a ‘trafficking’ problem of AMPARs to the synapse (Brechet A et al. (2017). Nat Commun 8, 1–14). The cognitive behaviour of ‘FRRS1l’ knock-out mice will be analysed in collaboration with Bernd Fakler (Freiburg University).

Furthermore, the NMDAR point mutation GluN2A(N615K), which was identified in a patient with strong mental retardation (Endele, S et al. (2010). Nat Genet 42, 1021–1026), will be analysed in knock-in mice. The oscillatory activity in the hippocampus and prefrontal cortex of our gene-targeted GluN2A(N615S) mouse model (for methods see [14]) should identify how the hippocampal -prefrontal cortex communication is affected and whether this communication could be 'normalised' by pharmacological treatment.

A mouse on the T.maze; a task that is used for the analysis pf special working memory? Genetiocally modified mice with altered glutamatergic transmission are used by Rolf Sprengel and his collaborators to identify connectivity impairments in his mouse models for schizophrenia and cognitive disorders.

2) Autism spectrum disorders (ASD): The over-expression of SHANK proteins or the expression of truncated SHANK is described as a causative gene mutations in some forms of ASD (Collaboration with Gudrun Rappold, Heidelberg University) and we could show that mice expressing virally transduced SHANK mutations show ASD like phenotypic behaviour [15]. Using conditional, transgenic mutagenesis [5] we have generated mice overexpressing different SHANK2 isoform in excitatory neurons of the forebrain. By switching off the over-expression of the SHANK2 proteins during and after development the group of Rolf Sprengel will identify which ASD-like phenotypes can be reversed by gene repair and which phenotypes are due to a developmental disorder. The classification into reversible and irreversible behavioural dysfunctions will have a strong impact on the therapeutic treatment and on the evaluation scheme of follow-up studies during or after treatment of ASD patients with SHANK mutations.

The postsynaptic scaffolding protein SHANK2 is involved in social competence in humans and mice. The conditional  mouse models of Rolf Sprengel’s Research group will identify neurodevelopment deficiencies mediated by inherited SHANK2 mutations.

3) Astroglia:  In close collaboration with Erlend Nagelhus (University of Oslo) we generated and used astrocyte specific rAAV-mediated gene expression to record astrocyte specific cellular activity in vitro and in vivo in a model of cortical spreading depression [16-18]. For network and cellular analysis of NMDA- and AMPA-receptor induced plasticity we developed and used rAAV-mediated delivery of genetic activity indicators together with Mazahir Hasan (Now In Bilbao, Spain). We are able to monitor, to manipulate and to analyse neuronal [19] and astroglial activity in mice on the cellular, neuronal network and behavioural level. In collaboration with Erlend Nagelhus group at the University of Oslo, 2-Photon imaging in awake mice will be used to dissect neuronal-glial cross-talk e.g. via an inducible neuronal silencing tool that Horst Obenhaus developed in the my group guided by the expertise and suggestions of Heinrich Betz [20]. In Heidelberg we are analysing the complexity astroglial activity pattern in acute brain slices trying to classify the different types of Ca2+-signal events observed in the somata, processes and end-feet. Here we are looking for correlations between, the different Ca2+-signalling events within the astrocytic network in relation to neuronal activity. By using brain slices from our mice with cognitive impairments, we will analyse whether the astroglia responses is related to cognitive impairments. This should reveal whether astroglial activity can be used as in vitro readout for hippocampal function in cognition. In addition, we are investigating the vesicle release in astrocytes using retrograde genetic tracers using rAAV gene-transfer.

All behavioural experiments of the group of Rolf Sprengel will be performed together with Claudia Pitzer at the Interdisciplinary Neurobehavioral Core (INCB) facility of the University Heidelberg.

All mouse lines of the research group of Rolf Sprengel are housed at the Interfaculty Biomedical Facility (IBF) of the University Heidelberg.

Correlated activity of neurons and astroglia cells can be monitored in the brain by genetic activity indicators, that response to increases intracellular Ca2+ levels. By rAAV-mediated gene transfer a red fluorescent genetic indicator was transferred to neurons and a green genetic indicator to astroglia cells. The simultaneous electrophysiological recording (position of the recording pipette is indicated by an arrow). Video taped time-laps recording of the green and red fluorescent reveal the correlation of glial and neuronal activity in acute brain slice of rAAV transduced mice.


External Grant support:

DFG-SFB1158/A05: Characteristics and consequences of subcellular calcium signaling in spinal neurons and glia in chronic inflammatory and neuropathic pain (08/2015 – 07/2019). (Sprengel). DFG-SFB1134/B01: Local and expanding glial activity patterns in memory-related networks of mice (01/2015 – 12/2018). (Sprengel). Dissecting neuronal-glial cross-talk via an inducible neuronal silencing tool (Oslo collaboration 2017-2021). 2- photon imaging of glial endfoot (dys)function in awake behaving mice (Oslo Collaboration 2016-2021).The still neglected brain cells: glia alive (Oslo Collaboration; 2015-2018). Ingeborg Ständer-Foundation: Deciphering the role of glutamatergic mechanisms in inhibitory versus excitatory neurons in inducible pharmacogenetic mouse models of schizophrenia.  (Collaboration with Central Institute for Mental Health in Mannheim, Sprengel, Inta).


LINKS Funding:

Research interest: Selected References (2013-2017)


(For complete Reference List please use the ‘Publication’ search option on my homepage)


1.   Freudenberg, F., Resnik, E., Kolleker, A., Celikel, T., Sprengel, R., and Seeburg, P.H. (2016) Hippocampal Glua1 Expression in Gria1-/- Mice Only Partially Restores Spatial Memory Performance Deficits. Neurobiol. Learn. Mem. (135):  83 - 90.


2.  Weber, T., Vogt, M.A., Gartside, S.E., Berger, S.M., Lujan, R., Lau, T., Herrmann, E., Sprengel, R., Bartsch, D., and Gass, P. (2015) Adult Ampa Glua1 Receptor Subunit Loss in 5-Ht Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-Ht Neuronal Activity. Neuropsychopharmacology (40):  1471-1484.


3.  Inta, D., Vogt, M.A., Elkin, H., Weber, T., Lima-Ojeda, J.M., Schneider, M., Luoni, A., Riva, M.A., Gertz, K., Hellmann-Regen, J., Kronenberg, G., Meyer-Lindenberg, A., Sprengel, R., and Gass, P. (2014) Phenotype of Mice with Inducible Ablation of Glua1 Ampa Receptors During Late Adolescence: Relevance for Mental Disorders. Hippocampus (24):  424-435.


4.   Freudenberg, F., Marx, V., Seeburg, P.H., Sprengel, R., and Celikel, T. (2013) Circuit Mechanisms of Glua1-Dependent Spatial Working Memory. Hippocampus (23):  1359-1366.


5.   Freudenberg, F., Marx, V., Mack, V., Layer, L.E., Klugmann, M., Seeburg, P.H., Sprengel, R., and Celikel, T. (2013) Glua1 and Its Pdz-Interaction: A Role in Experience-Dependent Behavioral Plasticity in the Forced Swim Test. Neurobiol. Dis. (52):  160-167.


6.   Vogt, M.A., Elkin, H., Pfeiffer, N., Sprengel, R., Gass, P., and Inta, D. (2014) Impact of Adolescent Glua1 Ampa Receptor Ablation in Forebrain Excitatory Neurons on Behavioural Correlates of Mood Disorders. Eur. Arch. Psychiatry Clin. Neurosci. (254):  625–629.


7.   Bygrave, A.M., Masiulis, S., Nicholson, E., Berkemann, M., Barkus, C., Sprengel, R., Harrison, P.J., Kullmann, D.M., Bannerman, D.M., and Katzel, D. (2016) Knockout of Nmda-Receptors from Parvalbumin Interneurons Sensitizes to Schizophrenia-Related Deficits Induced by Mk-801. Transl Psychiatry (6):  e778.


8.  Sanderson, D.J., Lee, A., Sprengel, R., Seeburg, P.H., Harrison, P.J., and Bannerman, D.M. (2017) Altered Balance of Excitatory and Inhibitory Learning in a Genetically Modified Mouse Model of Glutamatergic Dysfunction Relevant to Schizophrenia. Sci. Rep. (7):  1765.


9.   Boerner, T., Bygrave, A., Chen, J., Fernando, A., Jackson, S., Barkus, C., Sprengel, R., Seeburg, P.H., Harrison, P.J., Gilmour, G., Bannerman, D.M., and Sanderson, D.J. (2017) The Group Ii Metabotropic Glutamate Receptor Agonist Ly354740 and the D2 Receptor Antagonist Haloperidol Reduce Locomotor Hyperactivity but Fail to Rescue Spatial Working Memory in Glua1 Knockout Mice. Eur. J. Neurosci.


10. Lang, E., Mallien, A.S., Vasilescu, A.N., Hefter, D., Luoni, A., Riva, M.A., Borgwardt, S., Sprengel, R., Lang, U.E., Gass, P., and Inta, D. (2017) Molecular and Cellular Dissection of Nmda Receptor Subtypes as Antidepressant Targets. Neurosci. Biobehav. Rev.  [Epub ahead of print].


11. Taylor, A.M., Bus, T., Sprengel, R., Seeburg, P.H., Rawlins, J.N., and Bannerman, D.M. (2014) Hippocampal Nmda Receptors Are Important for Behavioural Inhibition but Not for Encoding Associative Spatial Memories. Philos. Trans. R. Soc. Lond. B Biol. Sci. (369):  20130149.


12. Bannerman, D.M., Sprengel, R., Sanderson, D.J., McHugh, S.B., Rawlins, J.N., Monyer, H., and Seeburg, P.H. (2014) Hippocampal Synaptic Plasticity, Spatial Memory and Anxiety. Nat. Rev. Neurosci. (15):  181-192.


13. Shimshek, D.R., Bus, T., Schupp, B., Jensen, V., Marx, V., Layer, L.E., Kohr, G., and Sprengel, R. (2017) Different Forms of Ampa Receptor Mediated Ltp and Their Correlation to the Spatial Working Memory Formation. Front. Mol. Neurosci. (10):  214.


14. Sprengel, R., Eltokhi, A., and Single, F.N., Gene Targeted Mice with Conditional Knock-in (-out) of Nmdar Mutations, in Nmda Receptors. Methods in Molecular Biology, Burnashev N. and S. P., Editors. 2017. p. 201-230.


15. Berkel, S., Tang, W., Trevino, M., Vogt, M., Obenhaus, H.A., Gass, P., Scherer, S.W., Sprengel, R., Schratt, G., and Rappold, G.A. (2012) Inherited and De Novo Shank2 Variants Associated with Autism Spectrum Disorder Impair Neuronal Morphogenesis and Physiology. Hum. Mol. Genet. (21):  344-357.


16. Enger, R., Dukefoss, D.B., Tang, W., Pettersen, K.H., Bjornstad, D.M., Helm, P.J., Jensen, V., Sprengel, R., Vervaeke, K., Ottersen, O.P., and Nagelhus, E.A. (2017) Deletion of Aquaporin-4 Curtails Extracellular Glutamate Elevation in Cortical Spreading Depression in Awake Mice. Cereb. Cortex (27):  24-33.


17. Enger, R., Tang, W., Vindedal, G.F., Jensen, V., Johannes Helm, P., Sprengel, R., Looger, L.L., and Nagelhus, E.A. (2015) Dynamics of Ionic Shifts in Cortical Spreading Depression. Cereb. Cortex (25):  4469-4476.


18. Tang, W., Szokol, K., Jensen, V., Enger, R., Trivedi, C.A., Hvalby, O., Helm, P.J., Looger, L.L., Sprengel, R., and Nagelhus, E.A. (2015) Stimulation-Evoked Ca2+ Signals in Astrocytic Processes at Hippocampal Ca3-Ca1 Synapses of Adult Mice Are Modulated by Glutamate and Atp. J. Neurosci. (35):  3016-3021


19. 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.


20. Obenhaus, H.A., Rozov, A., Bertocchi, I., Tang, W., Kirsch, J., Betz, H., and Sprengel, R. (2016) Causal Interrogation of Neuronal Networks and Behavior through Virally Transduced Ivermectin Receptors. Front. Mol. Neurosci. (9):  75.

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