Biology subjects

Ode, K. L.

Publications and source records attributed to Ode, K. L..

6 recordsLinked to original sources

bioRxiv2024

Boundary conditions for synaptic homeodynamics during the sleep-wake cycle

Understanding synaptic dynamics during the sleep-wake cycle is crucial yet remains controversial. The synaptic homeostasis hypothesis (SHY) suggests synaptic depression during non-rapid eye movement (NREM) sleep, while other studies report synaptic potentiation or synaptic changes during NREM sleep depending on activities in wakefulness. To find boundary conditions between these contradictory observations, we focused on learning rules and firing patterns that contribute to the synaptic dynamics. Using computational models, we found that under Hebbian and spike-timing dependent plasticity (STDP), wake-like firing patterns decrease synaptic weights, while sleep-like patterns strengthen synaptic weights. We refer to this tendency as Wake Inhibition and Sleep Excitation (WISE). Conversely, under Anti-Hebbian and Anti-STDP, synaptic depression during NREM sleep was observed, aligning with the conventional synaptic homeostasis hypothesis. Moreover, synaptic changes depended on firing rate differences between NREM sleep and wakefulness. We provide a unified framework that could explain synaptic homeodynamics under the sleep-wake cycle.

neuroscience↗

bioRxiv2024

A design principle of slow-wave sleep firing pattern with Na+ dynamics

Non-rapid eye movement (NREM) sleep is characterized by electroencephalography (EEG) signals with high amplitude and low frequency. This signal is thought to originate from the synchronized activity of cortical neurons, showing the alternating bursting state (up state) and resting state (down state). This activity is termed as slow-wave sleep (SWS) firing pattern. We previously proposed the importance of Ca2+-dependent hyperpolarization pathway in generating this firing pattern by introducing the averaged-neuron (AN) model, which describes neuronal activity based on the Hodgkin-Huxley type model. In the AN model, Ca2+-dependent K+ channels are involved in the transition from the up to the down state. Here we focus on the intracellular Na+ dynamics which are not explicitly described in the AN model. A revised AN model, termed as Na+-centered AN (NAN) model, proposes that the activation of voltage-gated Na+ channels leads to intracellular Na+ accumulation, which in turn triggers the activation of Na+-dependent K+ (KNa) channels or Na+/K+ ATPases, resulting in the down state. Changes in the activation kinetics of voltage-gated Na+ channels are important in shaping SWS firing pattern as well as explaining the inter-spike interval changes between SWS and AWAKE firing pattern. Mathematically, transition from the up state to the down state occurs in accordance with the change in the number of the fixed point in the dynamical system with the changes in the intracellular Na+ concentration. The importance of Na+-dependent pathway is elucidated even with the coexistence of Ca2+-dependent pathway. Subsequent analysis with network model suggests that the result of averaged neuron model with Na+ pathway can be extended to the population of neurons. Therefore, our model proposes that voltage-gated Na+ channels and Na+-dependent K+ channels or Na+/K+ ATPases are also the candidate pathways for the generation of SWS firing pattern.

systems biology↗

bioRxiv2023

Post-synaptic competition between calcineurin and PKA regulates mammalian sleep-wake cycles

Phosphorylation of synaptic proteins is a pivotal biochemical reaction that controls the sleep-wake cycle in mammals. Protein phosphorylation in vivo is reversibly regulated by kinases and phosphatases. In this study, we investigated a pair of kinases and phosphatases that reciprocally regulate sleep duration. Through comprehensive screening of Protein kinase A (PKA) and phosphoprotein phosphatase (PPP) family genes via the generation of 40 gene knockout mouse lines including post-natal CRISPR targeting, we identified a regulatory subunit of PKA (Prkar2b), a regulatory subunit of protein phosphatase (PP) 1 (Pppr1r9b), and catalytic and regulatory subunits of PP2B (calcineurin) (Ppp3ca and Ppp3r1) as sleep control genes. AAV-mediated stimulation of PKA and PP1/calcineurin activities confirmed PKA as a wake-promoting kinase, while PP1 and calcineurin function as sleep-promoting phosphatases. The importance of these phosphatases in sleep regulation is supported by the dramatic changes in sleep duration associated with their increased and decreased activity, ranging from approximately 17.3 hours/day (PP1 expression) to 6.7 hours/day (post-natal CRISPR targeting of calcineurin). For these phosphatases to exert their sleep-promoting effects, localization signals to the excitatory post-synapse were necessary. Furthermore, the wake-promoting effect of PKA localized to the excitatory post-synapse negated the sleep-promoting effect of calcineurin, suggesting that PKA and calcineurin construct a hierarchical phosphorylation control network for sleep regulation at excitatory post-synapses.

neuroscience↗

bioRxiv2023

Cortical parvalbumin neurons are responsible for homeostatic sleep rebound through CaMKII activation

The homeostatic regulation of sleep is characterized by rebound sleep after prolonged wakefulness, but the molecular and cellular mechanisms underlying this regulation are still unknown. We show here that CaMKII-dependent activity control of parvalbumin (PV)-expressing cortical neurons is involved in sleep homeostasis regulation. Prolonged wakefulness enhances cortical PV-neuron activity. Chemogenetic suppression or activation of cortical PV neurons inhibits or induces rebound sleep, implying that rebound sleep is dependent on increased activity of cortical PV neurons. Furthermore, we discovered that CaMKII kinase activity boosts the activity of cortical PV neurons, and that kinase activity is important for homeostatic sleep rebound. We propose that CaMKII-dependent PV-neuron activity represents negative feedback inhibition of cortical neural excitability, which serves as the distributive cortical circuits for sleep homeostatic regulation.

neuroscience↗

bioRxiv2022

Phosphorylation by casein kinase 2 ensures ER-phagy receptor TEX264 binding to ATG8 proteins

Selective autophagy cargos are recruited to autophagosomes primarily by interacting with autophagosomal ATG8 family proteins via the LC3-interacting region (LIR). The upstream sequence of most LIRs contains negatively charged residues such as Asp, Glu, and phosphorylated Ser and Thr. However, the significance of LIR phosphorylation (compared with having acidic amino acids) and the structural basis of phosphorylated LIR-ATG8 binding are not entirely understood. Here, we show that the serine residues upstream of the core LIR of the endoplasmic reticulum (ER)-phagy receptor TEX264 are phosphorylated by casein kinase 2, which is critical for its interaction with ATG8s, autophagosomal localization, and ER-phagy. Structural analysis showed that phosphorylation of these serine residues increased binding affinity by producing multiple hydrogen bonds with ATG8s that cannot be mimicked by acidic residues. This binding mode is different from those of other ER-phagy receptors that utilize a downstream helix, which is absent from TEX264, to increase affinity. These results suggest that phosphorylation of the LIR is critically important for strong LIR-ATG8 interactions, even in the absence of auxiliary interactions.

cell biology↗

bioRxiv2021

Realization of phosphorylation hypothesis of sleep by mammalian CaMKIIβ

The reduced sleep duration observed in Camk2a and Camk2b knockout mice revealed the role of Ca2+/calmodulin-dependent protein kinase II (CaMKII)/CAMKII{beta} as sleep-promoting kinases and lead to the phosphorylation hypothesis of sleep. However, the underlying mechanism of sleep regulation by kinases and protein phosphorylation is largely unknown. Here, we demonstrate that the phosphorylation states of CaMKII{beta} regulates sleep duration and sleep needs. Importantly, the activation or inhibition of CaMKII{beta} can increase or decrease sleep duration by almost two-fold, supporting the role of CaMKII{beta} as a core sleep regulator in mammals. This sleep regulation depends on the kinase activity of CaMKII{beta} in excitatory neurons. Furthermore, CaMKII{beta} mutants mimicking different phosphorylation states can regulate various sleep steps including sleep induction, sleep maintenance, and sleep cancelation. Key CaMKII{beta} residues responsible for the mode switch undergo ordered (auto-)phosphorylation. We thus propose that ordered multi-site phosphorylation of CaMKII{beta} underlies multi-step sleep regulation in mammals.

neuroscience↗