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 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.
Normandie Univ, UNICAEN, INSERM, Sérine protéases et physiopathologie de l'unité neurovasculaire, 14000 Caen, France.
Marie
M
Hébert
Normandie Univ, UNICAEN, INSERM, Sérine protéases et physiopathologie de l'unité neurovasculaire, 14000 Caen, France.
Antoine
A
Anfray
Normandie Univ, UNICAEN, INSERM, Sérine protéases et physiopathologie de l'unité neurovasculaire, 14000 Caen, France.
Arnaud
A
Chevilley
Normandie Univ, UNICAEN, INSERM, Sérine protéases et physiopathologie de l'unité neurovasculaire, 14000 Caen, France.
Sara
S
Martinez de Lizarrondo
Normandie Univ, UNICAEN, INSERM, Sérine protéases et physiopathologie de l'unité neurovasculaire, 14000 Caen, France.
Aurélien
A
Quenault
Normandie Univ, UNICAEN, INSERM, Sérine protéases et physiopathologie de l'unité neurovasculaire, 14000 Caen, France.
Morgane
M
Louessard
Normandie Univ, UNICAEN, INSERM, Sérine protéases et physiopathologie de l'unité neurovasculaire, 14000 Caen, France.
Benoit D
BD
Roussel
Normandie Univ, UNICAEN, INSERM, Sérine protéases et physiopathologie de l'unité neurovasculaire, 14000 Caen, France.
Pauline
P
Obiang
Laboratory of Cognitive Neuroscience UMR 7291, Aix-Marseille University, CNRS, 3 Place Victor Hugo, F-13331 Marseille Cedex 3, France.
Etienne
E
Save
Normandie Univ, UNICAEN, INSERM, Sérine protéases et physiopathologie de l'unité neurovasculaire, 14000 Caen, France.
Cyrille
C
Orset
Normandie Univ, UNICAEN, INSERM, Sérine protéases et physiopathologie de l'unité neurovasculaire, 14000 Caen, France.
Eric
E
Maubert
Normandie Univ, UNICAEN, INSERM, Sérine protéases et physiopathologie de l'unité neurovasculaire, 14000 Caen, France.|Biology Department, Clinical Research Department Medical Center, Normandie Université, UNICAEN, 14000 Caen, France.
Denis
D
Vivien
Normandie Univ, UNICAEN, INSERM, Sérine protéases et physiopathologie de l'unité neurovasculaire, 14000 Caen, France.
Véronique
V
Agin
D000375:Aging; D000818:Animals; D002118:Calcium / Q000378:metabolism; D018728:Entorhinal Cortex / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000378:metabolism
D016194:Receptors, N-Methyl-D-Aspartate; D010959:Tissue Plasminogen Activator; D002118:Calcium
N-methyl-D-aspartate receptor; aging; entorhinal cortex; spatial cognition; tissue plasminogen activator