Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aß by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like mice.

INTRODUCTION: Nav1.6 is closely related to the pathology of Alzheimer's Disease (AD), and astrocytes have recently been identified as a significant source of ß-amyloid (Aß). However, little is known about the connection between Nav1.6 and astrocyte-derived Aß. OBJECTIVE: This study explored the crucial role of Nav1.6 in mediated astrocyte-derived Aß in AD and knockdown astrocytic Nav1.6 alleviates AD progression by promoting autophagy and lysosome-APP fusion. METHODS: A mouse model for astrocytic Nav1.6 knockdown was constructed to study the effects of astrocytic Nav1.6 on amyloidosis. The role of astrocytic Nav1.6 on autophagy and lysosome-APP(amyloid precursor protein) fusion was used by transmission electron microscope, immunostaining, western blot and patch clamp. Glial cell activation was detected using immunostaining. Neuroplasticity and neural network were assessed using patch-clamp, Golgi stain and EEG recording. Behavioral experiments were performed to evaluate cognitive defects. RESULTS: Astrocytic Nav1.6 knockdown reduces amyloidosis, alleviates glial cell activation and morphological complexity, improves neuroplasticity and abnormal neural networks, as well as promotes learning and memory abilities in APP/PS1 mice. Astrocytic Nav1.6 knockdown reduces itself-derived Aß by promoting lysosome- APP fusion, which is related to attenuating reverse Na+-Ca2+ exchange current thus reducing intracellular Ca2+ to facilitate autophagic through AKT/mTOR/ULK pathway. CONCLUSION: Our findings unveil the crucial role of astrocyte-specific Nav1.6 in reducing astrocyte-derived Aß, highlighting its potential as a cell-specific target for modulating AD progression.

Claustrum modulates behavioral sensitivity and EEG activity of propofol anesthesia.

AIMS: The claustrum has long been regarded as a vital center for conscious control. Electrical stimulation or damage to the claustrum can result in decreased awareness or loss of consciousness, suggesting that the claustrum may be a target for the action of general anesthetics. This study aimed to determine the role of the claustrum in propofol anesthesia. METHODS: We first applied a fiber photometry calcium signal recording system to record the claustral neuronal activity during the entire process of propofol anesthesia. Chemogenetic activation of claustral neurones was then performed to verify their role in anesthesia. Finally, muscimol (GABAa receptor agonist) and gabazine (GABAa receptor antagonist) were microinjected into the claustrum to determine whether their GABAa receptors were involved in modulating propofol anesthesia. EEG and behavioral indicators, such as anesthetic sensitivity and efficacy, were recorded and analyzed. RESULTS: An evident anesthesia-related change in claustrum neuronal activity was suppressed during propofol-induced unconsciousness and restored following recovery from anesthesia. Chemogenetic activation of claustrum neurons results in attenuated propofol sensitivity, a shorter anesthesia duration, and an EEG shift toward wakefulness. Manipulation of GABAa receptors in the claustrum showed bidirectional control of propofol sensitivity, as activation decreases anesthesia efficiency while inactivation augments it. Additionally, inhibiting claustrum GABAa receptors increases cortical EEG slow waves. CONCLUSIONS: Claustrum neurones and their GABAa receptors are implicated in the modulation of propofol anesthesia in both behavioral and EEG assessments. Our findings create scope to reveal the brain targets of anesthetic action further and add to the existing evidence on the consciousness-modulating role of the claustrum.

Effect of basal forebrain somatostatin and parvalbumin neurons in propofol and isoflurane anesthesia.

AIMS: The basal forebrain (BF) plays an essential role in wakefulness and cognition. Two subtypes of BF gamma-aminobutyric acid (GABA) neurons, including somatostatin-expressing (GABASOM ) and parvalbumin-positive (GABAParv ) neurons, function differently in mediating the natural sleep-wake cycle. Since the loss of consciousness induced by general anesthesia and the natural sleep-wake cycle probably share similar mechanisms, it is important to clarify the accurate roles of these neurons in general anesthesia procedure. METHODS: Based on two transgenic mouse lines expressing SOM-IRES-Cre and PV-IRES-Cre, we used a combination of genetic activation, inactivation, and chronic ablation approaches to further explore the behavioral and electroencephalography (EEG) roles of BFSOM and BFParv neurons in general anesthesia. After a single intravenous injection of propofol and the induction and recovery times of isoflurane anesthesia, the anesthesia time was compared. The changes in cortical EEG under different conditions were also compared. RESULTS: Activation of BF GABASOM neurons facilitates both the propofol and isoflurane anesthesia, manifesting as a longer anesthesia duration time with propofol anesthesia and a fast induction time and longer recovery time with isoflurane anesthesia. Moreover, BF GABASOM -activated mice displayed a greater suppression of cortical electrical activity during anesthesia, showing an increase in δ power bands or a simultaneous decrease in high-frequency power bands. However, only a limited and nuanced effect on propofol and isoflurane anesthesia was observed with the manipulated BF GABAParv neurons. CONCLUSIONS: Our results suggested that BF GABASOM neurons play a critical role in propofol and isoflurane general anesthesia, while BF GABAParv neurons appeared to have little effect.

Basal Forebrain Cholinergic Activity Modulates Isoflurane and Propofol Anesthesia.

Cholinergic neurons in the basal forebrain (BF) have long been considered to be the key neurons in the regulation of cortical and behavioral arousal, and cholinergic activation in the downstream region of the BF can arouse anesthetized rats. However, whether the activation of BF cholinergic neurons can induce behavior and electroencephalogram (EEG) recovery from anesthesia is unclear. In this study, based on a transgenic mouse line expressing ChAT-IRES-Cre, we applied a fiber photometry system combined with GCaMPs expression in the BF and found that both isoflurane and propofol inhibit the activity of BF cholinergic neurons, which is closely related to the consciousness transition. We further revealed that genetic lesion of BF cholinergic neurons was associated with a markedly increased potency of anesthetics, while designer receptor exclusively activated by designer drugs (DREADD)-activated BF cholinergic neurons was responsible for slower induction and faster recovery of anesthesia. We also documented a significant increase in δ power bands (1-4 Hz) and a decrease in ß (12-25 Hz) power bands in BF cholinergic lesioned mice, while there was a clearly noticeable decline in EEG δ power of activated BF cholinergic neurons. Moreover, sensitivity to anesthetics was reduced after optical stimulation of BF cholinergic cells, yet it failed to restore wake-like behavior in constantly anesthetized mice. Our results indicate a functional role of BF cholinergic neurons in the regulation of general anesthesia. Inhibition of BF cholinergic neurons mediates the formation of unconsciousness induced by general anesthetics, and their activation promotes recovery from the anesthesia state.

Efficacy of different fluids preload on propofol injection pain: A randomized, controlled, double-blinded study.

Injection pain of propofol remains a common clinical problem. Previous studies demonstrated that propofol injection pain was alleviated by applying nitroglycerin ointment to the skin of injection site, which inspires us to test whether venous vasodilation induced by fluid preload could alleviate the pain. Different types or volumes of fluid preload were compared. 200 ASA I-II adult patients were randomly assigned to five groups of 40 each. A 20 G cannula was established on the dorsum or wrist of the hand. When fluid preload given with Plasma-Lyte A 100 mL (P100 group), 250 mL (P250 group), 500 mL (P500 group), 0.9% saline 500 mL (N500 group) or Gelofusine 500 mL (G500 group) was completed within 30 min, respectively, Propofol (0.5 mg/kg, 1%) was injected at a rate of 0.5 mL/s. A blind investigator assessed the pain using a four-point scale. Incidence of pain in P100, P250, and P500 groups was 87.5%, 57.5% and 35%, respectively (P<0.05). The median pain intensity score was significantly lower in P500 group than that in P250 and P100 groups (P<0.05 and P<0.01, respectively). Comparison of the effect of different types of solution preload indicated that the highest incidence of pain was in N500 group (62.5%) (N500 vs. P500, P=0.014; N500 vs. G500, P=0.007). The median pain intensity score in N500 group was higher than that in P500 group (P<0.05) and G500 group (P<0.05). There was no significant difference between P500 and G500 groups. It is suggested that Plasma-Lyte A or Gelofusine preload with 500 mL before propofol injection is effective in alleviating propofol-induced pain.