NGFN-PLUS
Transcriptional and posttranscriptional modifications
| Coordinator: | Dr. Rolf Sprengel | |
| Institution: | Max-Planck-Institut für medizinische Forschung, Heidelberg | |
| Homepage: | http://www.mpimf-heidelberg.mpg.de/groups/sprengel |
In our experimental approach we are analyzing the functional role of L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) und N-methyl-D-aspartate (NMDA) receptor mediated plasticity in learning and memory of mice (Bannerman DM et al. 2012, Nature Neuroscience 15, 1153–1159; Sanderson, DJ et al. 2008, Progress in Brain Research 169, 159–178). We are investigating whether the NMDA and AMPA receptor dependent learning underlies drug addiction. The molecular composition of the AMPA and NMDA receptor complex determines synaptic plasticity and the efficiency of excitatory neurotransmission which might be one basic subcellular, molecular mechanism of a leaning process in a neuronal network.
Our studies - using mice that lack the GluA1 containing AMPA receptor - provided the first evidence that GluA1 containing AMPA receptors significantly contribute to the correct decision when different memory contents are recalled by the animal in order to evaluate its current spatial position in the experimental environment (e.g. the short term spatial working memory and the long term memory (Sanderson DJ et al. 2010, Neuropsychologia 48, 2303–2315; Taylor AM et al. 2011, Behav Brain Res 224, 8–14; Sanderson, DJ et al. 2011, Learn Mem 18, 128–131; Sanderson DJ et al. 2011, Learn Mem 18, 181–190, Barkus C et al. 2012, Neuropharmacology 62, 1263–1272).
In drug addicted individuals the final emotional decision for drug consumption is strongly favored over the cognitive controlled avoidance of the drug. This “imbalance” of emotional versus cognitive decisions might be initiated and maintained by drug induced changes in AMPA and/or NMDA receptor signaling (Engblom D et al. 2008, Neuron 59, 497–508). But besides those changes that are introduced by alterations in the subunit combinations of the receptors, endogenous AMPA receptors modulating proteins might also be involved in drug induced behavioral changes.
In collaboration with the research unit of Prof. H. Monyer at the DKFZ / University Heidelberg, we identified a new family of proteins that can modulate the pharmacological profile of AMPA receptors. These proteins are membrane spanning and they contain an N-terminal Conotoxin like protein domain. Therefore, we called these AMPA receptor modifying proteins CKAMPs, standing for cystine-knot containing AMPA receptor modifying proteins (Engelhardt von J. et al. 2010, Science 327, 1518–1522).
In the frame work of this research consortium we are developing a gene targeted mouse model, that lack the best analyzed member of the CKAMP family, CKAMP44, and we generate transgenic mice that conditionally over-express CKAMP44 in principal neurons of the forebrain to analyze a putative role of CKAMP44 in learning and addiction.
Our studies - using mice that lack the GluA1 containing AMPA receptor - provided the first evidence that GluA1 containing AMPA receptors significantly contribute to the correct decision when different memory contents are recalled by the animal in order to evaluate its current spatial position in the experimental environment (e.g. the short term spatial working memory and the long term memory (Sanderson DJ et al. 2010, Neuropsychologia 48, 2303–2315; Taylor AM et al. 2011, Behav Brain Res 224, 8–14; Sanderson, DJ et al. 2011, Learn Mem 18, 128–131; Sanderson DJ et al. 2011, Learn Mem 18, 181–190, Barkus C et al. 2012, Neuropharmacology 62, 1263–1272).
In drug addicted individuals the final emotional decision for drug consumption is strongly favored over the cognitive controlled avoidance of the drug. This “imbalance” of emotional versus cognitive decisions might be initiated and maintained by drug induced changes in AMPA and/or NMDA receptor signaling (Engblom D et al. 2008, Neuron 59, 497–508). But besides those changes that are introduced by alterations in the subunit combinations of the receptors, endogenous AMPA receptors modulating proteins might also be involved in drug induced behavioral changes.
In collaboration with the research unit of Prof. H. Monyer at the DKFZ / University Heidelberg, we identified a new family of proteins that can modulate the pharmacological profile of AMPA receptors. These proteins are membrane spanning and they contain an N-terminal Conotoxin like protein domain. Therefore, we called these AMPA receptor modifying proteins CKAMPs, standing for cystine-knot containing AMPA receptor modifying proteins (Engelhardt von J. et al. 2010, Science 327, 1518–1522).
In the frame work of this research consortium we are developing a gene targeted mouse model, that lack the best analyzed member of the CKAMP family, CKAMP44, and we generate transgenic mice that conditionally over-express CKAMP44 in principal neurons of the forebrain to analyze a putative role of CKAMP44 in learning and addiction.
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