Bourtchouladze, R., Lidge, R., Catapano, R., Stanley, J., Gossweiler, S., Romashko, D., Scott, R., Tully, T. (September 2003) A mouse model of Rubinstein-Taybi syndrome: Defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. Proceedings of the National Academy of Sciences of the United States of America, 100 (18). pp. 10518-10522. ISSN 0027-8424
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Abstract
Mice carrying a truncated form of cAMP-responsive element binding protein (CREB)-binding protein (CBP) show several developmental abnormalities similar to patients with Rubinstein-Taybi syndrome (RTS). RTS patients suffer from mental retardation, whereas long-term memory formation is defective in mutant CBP mice. A critical role for cAMP signaling during CREB-dependent long-term memory formation appears to be evolutionarily conserved. From this observation, we reasoned that drugs that modulate CREB function by enhancing cAMP signaling might yield an effective treatment for the memory defect(s) of CBP+/- mice. To this end, we designed a cell-based drug screen and discovered inhibitors of phosphodiesterase 4 (PDE4) to be particularly effective enhancers of CREB function. We extend previous behavioral observations by showing that CBP+/- mutants have impaired long-term memory but normal learning and short-term memory in an object recognition task. We demonstrate that the prototypical PDE4 inhibitor, rolipram, and a novel one (HT0712) abolish the long-term memory defect of CBP+/- mice. Importantly, the genetic lesion in CBP acts specifically to shift the dose sensitivity for HT0712 to enhance memory formation, which conveys molecular specificity on the drug's mechanism of action. Our results suggest that PDE4 inhibitors may be used to treat the cognitive dysfunction of RTS patients.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | OBJECT RECOGNITION MEMORY TRANSCRIPTION FACTORS SPATIAL MEMORY CBP POTENTIATION HIPPOCAMPUS DROSOPHILA MUTATIONS DISCOVERY ROLIPRAM |
| Subjects: | diseases & disorders > congenital hereditary genetic diseases diseases & disorders organism description > animal behavior > memory diseases & disorders > congenital hereditary genetic diseases > mental retardation |
| CSHL Authors: | |
| Communities: | CSHL labs > Tully lab |
| Depositing User: | Matt Covey |
| Date: | September 2003 |
| Date Deposited: | 10 Jun 2013 19:56 |
| Last Modified: | 10 Sep 2019 18:37 |
| PMCID: | PMC193593 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27976 |
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