Homer1a and mGluR1/5 Signaling in Homeostatic Sleep Drive and Output.

Sleep is an essential physiological behavior that promotes cognitive development and function. Although the switch between sleep/wake cycles is controlled by specific neural circuits, sleep need and the restorative benefits of sleep are likely controlled by cellular mechanisms localized in critical areas of the brain involved in learning and memory including the cortex and hippocampus. However, the molecular basis for the restorative function(s) of sleep that support cognition, or for the homeostatic build-up of sleep need are poorly understood. Synapses undergo local and global changes in strength to support learning and memory and are likely a point of restoration during sleep. Homer1a and mGluR1/5, recently implicated in sleep function, are molecules involved in the scaling down process that weakens synapses during sleep to restore synapse homeostasis. During wake, long-form Homer proteins tether mGluR1/5 to IP3R and to the post-synaptic density (PSD). During sleep, short-form Homer1a uncouples mGluR1/5 from IP3R leaving mGluR1/5 open to interact with other effectors, switching mGluR1/5 signaling from "awake-type" to "sleep-type" signaling modes. Importantly, mGluR1/5 have been implicated in several neurological and neurodevelopmental disorders such as Alzheimer's disease (AD) and autism spectrum disorder (ASD), all of which show abnormal sleep phenotypes, linking sleep, disease, and mGluR1/5 signaling. Further investigation into the downstream effectors of mGluR1/5 and sleep/wake signaling will lead to more targeted therapeutic interventions.

Evaluating Fatty Acid Amide Hydrolase as a Suitable Target for Sleep Promotion in a Transgenic TauP301S Mouse Model of Neurodegeneration.

Sleep disruption is an expected component of aging and neurodegenerative conditions, including Alzheimer's disease (AD). Sleep disruption has been demonstrated as a driver of AD pathology and cognitive decline. Therefore, treatments designed to maintain sleep may be effective in slowing or halting AD progression. However, commonly used sleep aid medications are associated with an increased risk of AD, highlighting the need for sleep aids with novel mechanisms of action. The endocannabinoid system holds promise as a potentially effective and novel sleep-enhancing target. By using pharmacology and genetic knockout strategies, we evaluated fatty acid amide hydrolase (FAAH) as a therapeutic target to improve sleep and halt disease progression in a transgenic Tau P301S (PS19) model of Tauopathy and AD. We have recently shown that PS19 mice exhibit sleep disruption in the form of dark phase hyperarousal as an early symptom that precedes robust Tau pathology and cognitive decline. Acute FAAH inhibition with PF3845 resulted in immediate improvements in sleep behaviors in male and female PS19 mice, supporting FAAH as a potentially suitable sleep-promoting target. Moreover, sustained drug dosing for 5-10 days resulted in maintained improvements in sleep. To evaluate the effect of chronic FAAH inhibition as a possible therapeutic strategy, we generated FAAH-/- PS19 mice models. Counter to our expectations, FAAH knockout did not protect PS19 mice from progressive sleep loss, neuroinflammation, or cognitive decline. Our results provide support for FAAH as a novel target for sleep-promoting therapies but further indicate that the complete loss of FAAH activity may be detrimental.

Sleep Disruption Precedes Forebrain Synaptic Tau Burden and Contributes to Cognitive Decline in a Sex-Dependent Manner in the P301S Tau Transgenic Mouse Model.

Sleep disruption and impaired synaptic processes are common features in neurodegenerative diseases, including Alzheimer's disease (AD). Hyperphosphorylated Tau is known to accumulate at neuronal synapses in AD, contributing to synapse dysfunction. However, it remains unclear how sleep disruption and synapse pathology interact to contribute to cognitive decline. Here, we examined sex-specific onset and consequences of sleep loss in AD/tauopathy model PS19 mice. Using a piezoelectric home-cage monitoring system, we showed PS19 mice exhibited early-onset and progressive hyperarousal, a selective dark-phase sleep disruption, apparent at 3 months in females and 6 months in males. Using the Morris water maze test, we report that chronic sleep disruption (CSD) accelerated the onset of decline of hippocampal spatial memory in PS19 males only. Hyperarousal occurs well in advance of robust forebrain synaptic Tau burden that becomes apparent at 6-9 months. To determine whether a causal link exists between sleep disruption and synaptic Tau hyperphosphorylation, we examined the correlation between sleep behavior and synaptic Tau, or exposed mice to acute or chronic sleep disruption at 6 months. While we confirm that sleep disruption is a driver of Tau hyperphosphorylation in neurons of the locus ceruleus, we were unable to show any causal link between sleep loss and Tau burden in forebrain synapses. Despite the finding that hyperarousal appears earlier in females, female cognition was resilient to the effects of sleep disruption. We conclude sleep disruption interacts with the synaptic Tau burden to accelerate the onset of cognitive decline with greater vulnerability in males.

Sleep disruption precedes forebrain synaptic Tau burden and contributes to cognitive decline in a sex-dependent manner in the P301S Tau transgenic mouse model.

Background: Sleep is an essential process that supports brain health and cognitive function in part through the modification of neuronal synapses. Sleep disruption, and impaired synaptic processes, are common features in neurodegenerative diseases, including Alzheimer's disease (AD). However, the casual role of sleep disruption in disease progression is not clear. Neurofibrillary tangles, made from hyperphosphorylated and aggregated Tau protein, form one of the major hallmark pathologies seen in AD and contribute to cognitive decline, synapse loss and neuronal death.Tau has been shown to aggregate in synapses which may impair restorative synapse processes occurring during sleep. However, it remains unclear how sleep disruption and synaptic Tau pathology interact to drive cognitive decline. It is also unclear whether the sexes show differential vulnerability to the effects of sleep loss in the context of neurodegeneration. Methods: We used a piezoelectric home-cage monitoring system to measure sleep behavior in 3-11month-old transgenic hTau P301S Tauopathy model mice (PS19) and littermate controls of both sexes. Subcellular fractionation and Western blot was used to examine Tau pathology in mouse forebrain synapse fractions. To examine the role of sleep disruption in disease progression, mice were exposed to acute or chronic sleep disruption. The Morris water maze test was used to measure spatial learning and memory performance. Results: PS19 mice exhibited a selective loss of sleep during the dark phase, referred to as hyperarousal, as an early symptom with an onset of 3months in females and 6months in males. At 6months, forebrain synaptic Tau burden did not correlate with sleep measures and was not affected by acute or chronic sleep disruption. Chronic sleep disruption accelerated the onset of decline of hippocampal spatial memory in PS19 males, but not females. Conclusions: Dark phase hyperarousal is an early symptom in PS19 mice that precedes robust Tau aggregation. We find no evidence that sleep disruption is a direct driver of Tau pathology in the forebrain synapse. However, sleep disruption synergized with Tau pathology to accelerate the onset of cognitive decline in males. Despite the finding that hyperarousal appears earlier in females, female cognition was resilient to the effects of sleep disruption.

Tonic endocannabinoid signaling supports sleep through development in both sexes.

Sleep is an essential behavior that supports brain function and cognition throughout life, in part by acting on neuronal synapses. The synaptic signaling pathways that mediate the restorative benefits of sleep are not fully understood, particularly in the context of development. Endocannabinoids (eCBs) including 2-arachidonyl glycerol (2-AG) and anandamide (AEA), are bioactive lipids that activate cannabinoid receptor, CB1, to regulate synaptic transmission and mediate cognitive functions and many behaviors, including sleep. We used targeted mass spectrometry to measure changes in forebrain synaptic eCBs during the sleep/wake cycle in juvenile and adolescent mice of both sexes. We find that eCBs lack a daily rhythm in juvenile mice, while in adolescents AEA and related oleoyl ethanolamide are increased during the sleep phase in a circadian manner. Next, we manipulated the eCB system using selective pharmacology and measured the effects on sleep behavior in developing and adult mice of both sexes using a noninvasive piezoelectric home-cage recording apparatus. Enhancement of eCB signaling through inhibition of 2-AG or AEA degradation, increased dark-phase sleep amount and bout length in developing and adult males, but not in females. Inhibition of CB1 by injection of the antagonist AM251 reduced sleep time and caused sleep fragmentation in developing and adult males and females. Our data suggest that males are more sensitive to the sleep-promoting effects of enhanced eCBs but that tonic eCB signaling supports sleep behavior through multiple stages of development in both sexes. This work informs the further development of cannabinoid-based therapeutics for sleep disruption.