Human Alzheimer’s disease (AD) brains and transgenic AD mouse models manifest hyperexcitability. This aberrant electrical activity is caused by synaptic dysfunction that represents the major pathophysiological correlate of cognitive decline. However, the underlying mechanism for this excessive excitability remains incompletely understood. To investigate the basis for the hyperactivity, we performed electrophysiological and immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures and cerebral organoids bearing AD-related mutations in presenilin-1 or amyloid precursor protein vs. isogenic gene corrected controls. In the AD hiPSC-derived neurons/organoids, we found increased excitatory bursting activity, which could be explained in part by a decrease in neurite length. AD hiPSC-derived neurons also displayed increased sodium current density and increased excitatory and decreased inhibitory synaptic activity. Our findings establish hiPSC-derived AD neuronal cultures and organoids as a relevant model of early AD pathophysiology and provide mechanistic insight into the observed hyperexcitability.

SummarySleep is ancient and fulfills higher brain functions as well as basic vital processes. Little is known about how sleep emerged in evolution and what essential functions it was selected for. Here, we investigated sleep in Caenorhabditis elegans across developmental stages and physiological conditions to find out when and how sleep in a simple animal becomes essential for survival. We found that sleep in worms occurs during most stages and physiological conditions and is typically induced by the sleep-active RIS neuron. Food quality and availability determine sleep amount. Extended starvation, which induces developmental arrest in larvae, presents a major sleep trigger. Conserved nutrient-sensing regulators of longevity and developmental arrest, AMP-activated kinase and FoxO, act in parallel to induce sleep during extended food deprivation. These metabolic factors can act in multiple tissues to signal starvation to RIS. Although sleep does not appear to be essential for a normal adult lifespan, it is crucial for survival of starvation-induced developmental arrest in larvae. Rather than merely saving energy for later use, sleep counteracts the progression of aging phenotypes, perhaps by allocating resources. Thus, sleep presents a protective anti-aging program that is induced by nutrient-sensing longevity pathways to survive starvation-induced developmental arrest. All organisms are threatened with the possibility of experienced famine in their life, which suggests that the molecular coupling of starvation, development, aging, and sleep was selected for early in the evolution of nervous systems and may be conserved in other species, including humans.

Objective Dietary loading has been reported to have an effect on temporomandibular joint (TMJ) remodeling via periodontal-muscular reflex. We therefore examined whether reducing dietary loading decreased TMJ degradation induced by the unilateral anterior crossbite prosthesis as we recently reported. Methods Forty 6-week-old female C57BL/6J mice were randomly divided into two experimental and two control groups. One experimental and one control group received small-size diet and the other two groups received large-size diet. Unilateral anterior crossbite prosthesis was created in the two experimental groups. The TMJ samples were collected 3 weeks after experimental operation. Histological changes in condylar cartilage and subchondral bone were assessed by Hematoxylin & Eosin, toluidine blue, Safranin O and tartrate-resistant acid phosphatase staining. Real-time polymerase chain reaction (PCR) and/or immunohistochemistry were performed to evaluate the expression levels of Collagen II, Aggrecan, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) and RANKL/RANK/OPG in TMJ condylar cartilage and/or subchondral bone. Results Thinner and degraded cartilage, reduced cartilage cellular density, decreased expression levels of Collagen II and Aggrecan, loss of subchondral bone and enhanced osteoclast activity were observed in TMJs of both experimental groups. However, the cartilage degradation phenotype was less severe and cartilage ADAMTS-5 mRNA was lower while OPG/RANKL ratio in cartilage and subchondral bone was higher in the small-size than large-size diet experimental group. No differences of histomorphology and the tested molecules were found between the two control groups. Conclusions The current findings suggest that a lower level of functional loading by providing small-size diet could reduce TMJ degradation induced by the biomechanical stimulation from abnormal occlusion.

Beginning at early stages, human Alzheimer’s disease (AD) brains manifest hyperexcitability, contributing to subsequent extensive synapse loss, which has been linked to cognitive dysfunction. No current therapy for AD is disease-modifying. Part of the problem with AD drug discovery is that transgenic mouse models have been poor predictors of potential human treatment. While it is undoubtedly important to test drugs in these animal models, additional evidence for drug efficacy in a human context might improve our chances of success. Accordingly, in order to test drugs in a human context, we have developed a platform of physiological assays using patch-clamp electrophysiology, calcium imaging, and multielectrode array (MEA) experiments on human (h)iPSC-derived 2D cortical neuronal cultures and 3D cerebral organoids. We compare hiPSCs bearing familial AD mutations vs. their wild-type (WT) isogenic controls in order to characterize the aberrant electrical activity in such a human context. Here, we show that these AD neuronal cultures and organoids manifest increased spontaneous action potentials, slow oscillatory events (~1 Hz), and hypersynchronous network activity. Importantly, the dual-allosteric NMDAR antagonist NitroSynapsin, but not the FDA-approved drug memantine, abrogated this hyperactivity. We propose a novel model of synaptic plasticity in which aberrant neural networks are rebalanced by NitroSynapsin. We propose that hiPSC models may be useful for screening drugs to treat hyperexcitability and related synaptic damage in AD.