Distant Space Processing is Controlled by tPA-dependent NMDA Receptor Signaling in the Entorhinal Cortex

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 hippocamp...

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Published in:Cerebral cortex (New York, N.Y. 1991) N.Y. 1991), 2017-10, Vol.27 (10), p.4783-4796
Main Authors: Hébert, Marie, Anfray, Antoine, Chevilley, Arnaud, Martinez de Lizarrondo, Sara, Quenault, Aurélien, Louessard, Morgane, Roussel, Benoit D, Obiang, Pauline, Save, Etienne, Orset, Cyrille, Maubert, Eric, Vivien, Denis, Agin, Véronique
Format: Article
Language:English
Subjects:
Aging
Animals
Calcium - metabolism
Entorhinal Cortex - metabolism
Female
Hippocampus - metabolism
Life Sciences
Male
Mice, Knockout
Neurons - metabolism
Neurons and Cognition
Receptors, N-Methyl-D-Aspartate - metabolism
Signal Transduction - physiology
Tissue Plasminogen Activator - deficiency
Tissue Plasminogen Activator - metabolism
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Summary: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.
ISSN:1047-3211
1460-2199
DOI:10.1093/cercor/bhw275