Die Rolle von Glutamat und Glutamatrezeptoren in Mausmodellen für emotionales Verhalten und affektive Störungen
Zusammenfassung der Projektergebnisse
Using mice with deletions of specific glutamate receptor subunits we studied their role in mouse models for emotional behaviors and mood disorders as well as different aspects of cognitive behavior. Moreover, we investigated molecular, neuroendocrinological and pharmacological aspects in these models following stress exposure. As a first result we could demonstrate, that mice lacking the AMPA receptor subunit GluA1 – which have a deficit in LTP – have severe deficits in short-term but not long-term spatial memory. This supports the so-called competitive memory hypothesis, predicting that the evaluation of competing memories is dependent of GluA1 containing AMPA receptors. This lack of expression of short-term memory could also account for behavioral impairments during stress or depression: “the reality value is over- or underestimated in presence of the strong stress or depression memory”. Indeed, we obtained evidence that GluA1 KO mice show increased learned helplessness which is paralleled by decreased serotonin and norepinephrine levels, and disturbed glutamate homeostasis with increased glutamate levels and increased NMDA receptor expression in stressed GluA1 deficient mice compared to controls. The behavioral phenotype of GluA1 KO mice could be partially rescued by treatment with lithium. On the molecular level acute stress increased in GluA1 KO mice hippocampal expression of Arc (activityregulated cytoskeletal-associated protein) and phospho-CaMKII, together with the phosphorylation of the main NMDA receptor subunits GluN1, GluN2A and GluN2B in wildtype mice indicating that NMDA receptor induced transcriptional and posttranslational modifications of key molecules for synaptic plasticity are activated. These findings suggest that the integrity of AMPA/NMDA receptor signaling is important for successful evaluation of different kinds of memories that are activated under stressful conditions, working memory tasks and traumatic/stressful events inducing depression. Subtype specific drugs, specific for AMPA receptors containing the GluA1 subunit might be powerful tools for treatment of these disorders. With respect to NMDA receptor subunits, we used brain region selective mutations in hippocampus and amygdala to analyze their function for emotional learning under stress in fear conditioning experiments by virus mediated gene inactivation. The doxycycline-inducible neuronspecific system was used for synaptic silencing of neurons in the amygdala, and to inactivate NMDA receptors in the basolateral nucleus of the amygdala (BLA). Altogether, the analysis of rAAV-injected mice provided strong evidence that retrieval of cued fear memory is dependent on the chronic expression of NMDA receptors in the BLA.
Projektbezogene Publikationen (Auswahl)
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(2008) Genetic interference to study amygdala function in mice. PhD Thesis, University Heidelberg
Bosch, V.
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(2008). AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression. FASEB J 22, 3129-3134
Chourbaji, S., Vogt, M.A., Fumagalli, F., Sohr, R., Frasca, A., Brandwein, C., Hörtnagl, H., Riva, M.A., Sprengel, R., and Gass, P.
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(2009). Differential c-Fos induction by different NMDA receptor antagonists with antidepressant efficacy: potential clinical implications. J Neuropsychopharmacol 12, 1133-1136
Inta, D., Trusel, M., Riva, M.A., Sprengel, R., and Gass, P.
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(2009). Enhanced long-term and impaired short-term spatial memory in GluA1 AMPA receptor subunit knockout mice: evidence for a dual-process memory model. Learn Mem 16, 379-386
Sanderson, D.J., Good, M.A., Skelton, K., Sprengel, R., Seeburg, P.H., Rawlins, J.N.P., and Bannerman, D.M.
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(2009). Faithful expression of multiple proteins via 2A-peptide self-processing: a versatile and reliable method for manipulating brain circuits. J Neurosci 29, 8621-8629
Tang, W., Ehrlich, I., Wolff, S.B.E., Michalski, A.-M., Wölfl, S., Hasan, M.T., Lüthi, A., and Sprengel, R.
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(2010). Does gene deletion of AMPA GluA1 phenocopy features of schizoaffective disorder? Neurobiol Dis 40, 608-621
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.
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(2010). Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion. Eur J Pharmacol 626, 49-56
Barkus, C., McHugh, S.B., Sprengel, R., Seeburg, P.H., Rawlins, J.N.P., and Bannerman, D.M.
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(2010). Spatial working memory deficits in GluA1 AMPA receptor subunit knockout mice reflect impaired short-term habituation: evidence for Wagner’s dual-process memory model. Neuropsychologia 48, 2303-2315
Sanderson, D.J., McHugh, S.B., Good, M.A., Sprengel, R., Seeburg, P.H., Rawlins, J.N.P., and Bannerman, D.M.
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(2011). Deletion of the GluA1 AMPA receptor subunit alters the expression of short-term memory. Learn Mem 18, 128-131
Sanderson, D.J., Sprengel, R., Seeburg, P.H., and Bannerman, D.M.
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2011, Genetic analysis of emotional memory in AMPA and NMDA receptor mutant mice. PhD Thesis, University Heidelberg
Arcos-Diaz, D.
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(2012). Sensorimotor gating working and social memory deficits in mice with reduced expression of the vesicular glutamate transporter VGLUT1. Behav Brain Res, 228: 328-332
Inta, D., Vogt, M.A., Perreau-Lenz, S., Schneider, M., Pfeiffer, N., Wojcik, S., Brose, N., Spanagel R., and Gass, P.
