期刊
CEREBRAL CORTEX
卷 27, 期 10, 页码 4783-4796出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhw275
关键词
aging; entorhinal cortex; N-methyl-D-aspartate receptor; spatial cognition; tissue plasminogen activator
资金
- INSERM (French National Institute for Health and Medical Research)
- Trans Channel Neuroscience Network (TC2N)
- Seventh Framework Programme for Research and Technological Development [FP7 NEURON 3-275-006]
- Foundation for Medical Research (FRM) [DEQ20140329555]
- Regional Council of Lower Normandy
In humans, spatial cognition and navigation impairments are a frequent situation during physiological and pathological aging, leading to a dramatic deterioration in the quality of life. Despite the discovery of neurons with location-specific activity in rodents, that is, place cells in the hippocampus and later on grid cells in the entorhinal cortex (EC), the molecular mechanisms underlying spatial cognition are still poorly known. Our present data bring together in an unusual combination 2 molecules of primary biological importance: a major neuronal excitatory receptor, N-methyl-D-aspartate receptor (NMDAR), and an extracellular protease, tissue plasminogen activator (tPA), in the control of spatial navigation. By using tPA-deficient mice and a structure-selective pharmacological approach, we demonstrate that the tPA-dependent NMDAR signaling potentiation in the EC plays a key and selective role in the encoding and the subsequent use of distant landmarks during spatial learning. We also demonstrate that this novel function of tPA in the EC is reduced during aging. Overall, these results argue for the concept that encoding of proximal versus distal landmarks is mediated not only by different anatomical pathways but also by different molecular mechanisms, with the tPA-dependent potentiation of NMDAR signaling in the EC that plays an important role.
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