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J Neurosci. 2019 May 13. pii: 2876-18. doi: 10.1523/JNEUROSCI.2876-18.2019. [Epub ahead of print]

The p75 neurotrophin receptor is an essential mediator of impairments in hippocampal-dependent associative plasticity and memory induced by sleep deprivation.

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Department of Physiology, National University of Singapore, Singapore 117597, Singapore.
Neurobiology/Aging Program, Life Sciences Institute, National University of Singapore, Singapore 117 456.
Department of Cell and Molecular Biology, Karolinska Institute, Stockholm S-17177, Sweden.
Department of Physiology, National University of Singapore, Singapore 117597, Singapore


Sleep deprivation (SD) interferes with hippocampal structural and functional plasticity, formation of long-term memory (LTM) and cognitive function. The molecular mechanisms underlying these effects are incompletely understood. Here, we show that SD impaired synaptic tagging and capture (STC) and behavioral tagging (BT), two major mechanisms of associative learning and memory. Strikingly, mutant male mice lacking the p75 neurotrophin receptor (p75NTR) were resistant to the detrimental effects of SD on hippocampal plasticity at both cellular and behavioral levels. Mechanistically, SD increased p75NTR expression and its interaction with phosphodiesterase (PDE4A5). p75NTR deletion preserved hippocampal structural and functional plasticity by preventing SD-mediated effects on hippocampal cAMP-CREB-BDNF, cAMP-PKA-LIMK1-cofilin and RhoA-ROCK2 pathways. Our study identifies p75NTR as an important mediator of hippocampal structural and functional changes associated with SD, and suggests that targeting p75NTR could be a promising strategy to limit the memory and cognitive deficits that accompany sleep loss.SIGNIFICANCE STATEMENTThe lack of sufficient sleep is a major health concern in today's world. Sleep deprivation (SD) affects cognitive functions such as memory. We have investigated how associative memory mechanisms, synaptic tagging and capture (STC), was impaired in SD mice at cellular and behavioral level. Interestingly, mutant male mice that lacked the p75 neurotrophin receptor (p75NTR) were seen to be resistant to the SD-induced impairments in hippocampal synaptic plasticity and STC. Additionally, we elucidated the molecular pathways responsible for this rescue of plasticity in the mutant mice. Our study has thus identified p75NTR as a promising target to limit the cognitive deficits associated with SD.

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