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

Abstract

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.

Disentangling the Role of the MEC and LEC in the Processing of Spatial and Non-Spatial Information: Contribution of Lesion Studies

“…Rats with EC lesions were not able to learn the task using distal landmarks but were able to do it using proximal landmarks. Consistent results were provided in a recent study (Hébert et al, 2017 ), investigating the effects induced by genetic of pharmacological blockade within the EC of an extracellular protease (the tissue plasminogen activator—tPA), in two spatial tasks: the Morris Water maze task and a 2-trial place recognition task in a T-maze. Intra-EC inactivation of the tPA provoked deficits in both tasks when the animals had to use distal landmarks.…”

Are Distal and Proximal Visual Cues Equally Important during Spatial Learning in Mice? A Pilot Study of Overshadowing in the Spatial Domain

“…Whereas the one devoted to the processing of distal cues is dependent on the entorhinal cortex (EC) per se , the one devoted to the processing of proximal cues requires the activation of the associative parietal cortex (APC). We recently extended these results by showing that the encoding of proximal vs. distal landmarks is mediated not only by different anatomical pathways, but also by different molecular mechanisms with tissue-type plasminogen activator (tPA)-dependent N-methyl-D-aspartate receptor signaling pathway in the EC playing a key role in distal but not proximal landmark processing (Hébert et al, 2016). In this same study, we have also provided the first evidence of the occurrence of a negative tone exerted by tPA-related EC/hippocampus-dependent pathway on the APC/hippocampus-dependent pathway.…”

“…Therefore, in order to efficiently perform multifactorial analyses, the results could be duplicated using behavioral tools adapted to the detection of intergroup effects such as the Morris water-maze or the radial-maze. Second, the two-trial place recognition procedure was mainly used to assess genetic variability as well as cellular and molecular bases of spatial learning in rodents (Dellu et al, 1992, 2000; Obiang et al, 2011, 2012; Hébert et al, 2016). The effects reported in these publications can therefore reasonably be assumed to be far larger than the one observed in our study, where some fine difference in behavior has to be assessed between otherwise similar healthy mice.…”

Post-synaptic Release of the Neuronal Tissue-Type Plasminogen Activator (tPA)

“…In addition to its roles in the vascular system, tPA plays crucial functions in the central nervous system (CNS) acting either as an enzyme or as a growth-factor-like molecule (Thiebaut et al, 2018). Thus, tPA is involved in several physiological and pathological CNS processes, including corticogenesis, neuronal survival, learning and memory, anxiety, epilepsy, stroke and Alzheimer's disease (Qian et al, 1993; Baranes et al, 1998; Madani et al, 1999; Pawlak et al, 2003; Alvarez et al, 2013; Oh et al, 2014; Hébert et al, 2017; Pasquet et al, 2018). Its neuronal functions are achieved through plasminogen-dependent or plasminogen-independent effects (Melchor and Strickland, 2005).…”