The p75 Neurotrophin Receptor Is an Essential Mediator of Impairments in Hippocampal-Dependent Associative Plasticity and Memory Induced by Sleep Deprivation

Abstract

Sleep deprivation (SD) interferes with hippocampal structural and functional plasticity, formation of long-term memory and cognitive function. The molecular mechanisms underlying these effects are incompletely understood. Here, we show that SD impaired synaptic tagging and capture and behavioral tagging, two major mechanisms of associative learning and memory. Strikingly, mutant male mice lacking the p75 neurotrophin receptor (p75 NTR ) were resistant to the detrimental effects of SD on hippocampal plasticity at both cellular and behavioral levels. Mechanistically, SD increased p75 NTR expression and its interaction with phosphodiesterase. p75 NTR 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 p75 NTR as an important mediator of hippocampal structural and functional changes associated with SD, and suggests that targeting p75 NTR could be a promising strategy to limit the memory and cognitive deficits that accompany sleep loss.The 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 (p75 NTR ) 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 p75 NTR as a promising target to limit the cognitive deficits associated with SD.

p75NTR as a Molecular Memory Switch

“…While a previous work established that circadian rhythm can regulate the transcriptional activation of p75NTR in the nervous system and peripheral tissues, indicating its role in maintenance of the circadian clock and metabolic gene oscillation, the association between p75NTR and sleep deprivation in synaptic plasticity and cognitive decline was not investigated (12). In their paper, Wong et al (8) showed that sleep deprivation could impair crucial synaptic processes that are necessary for associative learning and memory. Furthermore, they found that sleep deprivation modulates the RhoA-ROCK2 and cAMP-PKA-LIMK1-cofilin pathways via p75NTR.…”

“…Notably, previous studies investigated the molecular underpinnings and found that sleep deprivation selectively impaired cAMP/PKA-dependent forms of synaptic plasticity in the hippocampus to reduce cAMP signaling and increase phosphodiesterase-4 activity, which degrades cAMP (15). One key finding in the recently published paper by Wong et al (8) is that p75NTR confers a protective effect on late LTP deficits induced by sleep deprivation. Sleep deficiency can cause LTP deficits, specifically STC deficits.…”

Phosphodiesterase inhibitors roflumilast and vardenafil prevent sleep deprivation‐induced deficits in spatial pattern separation

“…The negative impact of SD on hippocampal function is at least partly caused by increased phosphodiesterase (PDE) activity and related suppression of cAMP signaling (Havekes et al, ; Havekes, Park, Tolentino, et al, ; Vecsey et al, ). Because cGMP and cAMP signaling potentially target the same downstream signaling molecules known to be affected by SD (i.e., CREB (Wong, Tann, Ibanez, & Sajikumar, ), LIMK1‐cofilin (Havekes, Park, Tudor, et al, ; Wong et al, ; Zulauf et al, )), cGMP signaling may also be a relevant therapeutic target in this respect. While disrupting effects of SD have been reported for a variety of hippocampal tasks (Havekes & Abel, ; Havekes, Meerlo, & Abel, ), its impact on pattern separation remains to be defined.…”

“…Because cGMP and cAMP signaling potentially target the same downstream signaling molecules known to be affected by SD (i.e., CREB (Wong et al, ), LIMK1‐cofilin (Havekes, Park, Tudor, et al, )), as a next step we targeted cGMP signaling using the PDE5 inhibitor vardenafil. Vardenafil has previously shown to increase cGMP in the hippocampus and improve the memory function in rodents (Akkerman et al, ).…”

“…The role of cGMP and its downstream effectors in spatial pattern separation is currently unknown and to our knowledge, no studies have examined the impact of SD on cGMP signaling in this respect. However, both cyclic nucleotide pathways are known to converge on the CREB and LIMK1‐cofilin pathways (Havekes, Park, Tudor, et al, ; Wong et al, ; Zulauf et al, ), known to play a causal role in the memory and plasticity phenotypes associated with SD. For this reason, it may very well be that treatment with vardenafil prevents deficits in patterns’ separation by acting on the aforementioned signaling pathways.…”