Meprin β modulates brevican proteolysis impairing neural plasticity and memory formation

Abstract

The metalloprotease meprin β is known for its multifunctional involvement in various physiological processes throughout the body including the brain. However, its broader functions within the brain besides amyloid β generation remain largely unexplored. To investigate this, we utilized a mouse model overexpressing meprin β in neurons within the cortex and hippocampus, regions crucial for learning and memory. Behavioral assessments, employing the Morris' Water Maze paradigm test, revealed impaired cognitive functions in animals overexpressing meprin β. Furthermore, electrophysiological recordings in hippocampal slices using multielectrode arrays showed an impaired long-term potentiation (LTP) in meprin β-overexpressing mice compared to wild-type counterparts. Intriguingly, concomitant with the LTP impairment, we observed an increased neuronal excitability. These findings underline the complicated interplay between meprin β abundance and behavioral manifestations, suggesting a broader impact on neural circuit dynamics. To elucidate the molecular mechanisms underlying these observed deficits, western blotting analyses were conducted to address the expression of glutamatergic receptors. Neither the expression of the N-methyl-D-aspartate (NMDA) nor the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor showed variation relative to each other. The application of N-terminomics identified brevican as a proteolytic substrate of meprin β and thus a potential key mediator linking meprin β overexpression to the observed effects. Previous studies have reported that brevican knockout in animal models influences learning and memory. Our data demonstrate that meprin β modulates brevican expression, likely contributing to the effects we have observed in our mouse model. These results shed light on the broader functional significance of meprin β in neurological processes.