A Developmental Role for Microglial Presenilin 1 in Memory

Summary Microglia, the macrophages of the brain, are increasingly recognized to play a key role in synaptic plasticity and function; however, the underlying mechanisms remain elusive. Presenilin 1 (PS1) is an essential protein involved in learning and memory, through neuronal mechanisms. Loss of Pre...

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Published inbioRxiv
Main Authors Ledo, Jose Henrique, Azevedo, Estefania P, Medrihan, Lucian, Cheng, Jia, Silva, Hernandez M, Mccabe, Kathryn, Bamkole, Michael, Lafaille, Juan J, Friedman, Jeffrey M, Stevens, Beth, Greengard, Paul
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 27.01.2021
Subjects
Alzheimer's disease
Calcium imaging
Cognitive ability
Glutamic acid receptors (ionotropic)
Learning
Macrophages
Memory
Microglia
N-Methyl-D-aspartic acid receptors
Neurodegenerative diseases
Neuroimaging
Neuromodulation
Presenilin 1
Synaptic plasticity
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Summary:Summary Microglia, the macrophages of the brain, are increasingly recognized to play a key role in synaptic plasticity and function; however, the underlying mechanisms remain elusive. Presenilin 1 (PS1) is an essential protein involved in learning and memory, through neuronal mechanisms. Loss of Presenilin function in neurons impairs synapse plasticity and causes cognitive deficits in mice. Surprisingly, here we show memory enhancement in mice by deleting PS1 selectively in microglia. We further demonstrate increased synapse transmission and in vivo neuronal activity in mice by depleting PS1 during microglial development, but not after microglial maturation. Remarkably, conditional deletion of PS1 in microglia during development increased memory retention in adulthood and was dependent on the NMDA receptor subunit GluN2B. In vivo calcium imaging of freely behaving mice revealed increased amplitude of neuronal Ca2+ transients in the CA1 hippocampus of PS1 cKO mice compared to control mice, suggesting a greater CA1 engagement during novel object exploration. Finally, loss of PS1 in microglia mitigated synaptic and cognitive deficits in a mouse model of Alzheimer’s disease. Together our results reveal a novel mechanism and function of PS1 in microglia in which modulation can enhance neuronal activity, learning and memory in mice. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2021.01.26.428181