Ligand-dependent TrkA activity in brain differentially affects spatial learning and long-term memory
| Autor: | Edith Hamel, Xin-Kang Tong, Kenneth E. Neet, Fouad Brahimi, Yiu Chung Tse, H. Uri Saragovi, Tak Pan Wong, Tahar Aboulkassim, Sang B. Woo |
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| Rok vydání: | 2011 |
| Předmět: |
Pharmacology
Memory Long-Term Long-term memory Blotting Western Hippocampus Enzyme-Linked Immunosorbent Assay Mice Transgenic Tropomyosin receptor kinase A Biology Ligands Mice Nerve growth factor nervous system Neurotrophic factors biology.protein Molecular Medicine Low-affinity nerve growth factor receptor Animals Learning Cholinergic neuron Receptor trkA Neuroscience Neurotrophin |
| Zdroj: | Molecular pharmacology. 80(3) |
| ISSN: | 1521-0111 |
| Popis: | In the central nervous system, the nerve growth factor (NGF) receptor TrkA is expressed primarily in cholinergic neurons that are implicated in spatial learning and memory, whereas the NGF receptor p75(NTR) is expressed in many neuronal populations and glia. We asked whether selective TrkA activation may have a different impact on learning, short-term memory, and long-term memory. We also asked whether TrkA activation might affect cognition differently in wild-type mice versus mice with cognitive deficits due to transgenic overexpression of mutant amyloid-precursor protein (APP mice). Mice were treated with wild-type NGF (a ligand of TrkA and p75(NTR)) or with selective pharmacological agonists of TrkA that do not bind to p75(NTR). In APP mice, the selective TrkA agonists significantly improved learning and short-term memory. These improvements are associated with a reduction of soluble Aβ levels in the cortex and AKT activation in the cortex and hippocampus. However, this improved phenotype did not translate into improved long-term memory. In normal wild-type mice, none of the treatments affected learning or short-term memory, but a TrkA-selective agonist caused persistent deficits in long-term memory. The deficit in wild-type mice was associated temporally, in the hippocampus, with increased AKT activity, increased brain-derived neurotrophic factor precursor, increased neurotrophin receptor homolog-2 (p75-related protein), and long-term depression. Together, these data indicate that selective TrkA activation affects cognition but does so differently in impaired APP mice versus normal wild-type mice. Understanding mechanisms that govern learning and memory is important for better treatment of cognitive disorders. |
| Databáze: | OpenAIRE |
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