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Bergamot essential oil (BEO) is an extract of the bergamot fruit with significant neuroprotective effect. This study was to investigate the effects and the underlying mechanism of BEO in mitigating depression. GC–MS were used to identify its constituents. Antidepressive properties of BEO were evaluated by sucrose preference test (SPT), force swimming test (FST) and open field test (OFT). Nissl staining was used to determine the number of Nissl bodies in hippocampus (HIPP) of rats. Changes in HIPP dendritic length and dendritic spine density were detected by Golgi‐Cox staining. Immunohistochemistry and Western blot were used to detect the postsynaptic density protein‐95 (PSD‐95) and synaptophysin (SYP) in the HIPP of rats. The enzyme‐linked immunosorbent assay was used to determine the 5‐hydroxytryptamine (5‐HT), insulin‐like growth factor 1 (IGF‐1) and interleukin‐1β (IL‐1β) in the HIPP, serum and cerebrospinal fluid (CSF) of rats. Inhaled BEO significantly improved depressive behaviour in chronic unpredictable mild stress (CUMS) rats. BEO increased Nissl bodies, dendritic length and spine density, PSD‐95 and SYP protein in the HIPP. Additionally, BEO upregulated serum 5‐HT, serum and CSF IGF‐1, while downregulating serum IL‐1β. Collectively, inhaled BEO mitigates depression by protecting the plasticity of hippocampal neurons, hence, providing novel insights into treatment of depression.

Cerebral ischemia activates an endogenous repair program that induces plastic changes in neurons. In this study, we investigated the effects of environmental enrichment on spatial learning and memory as well as on synaptic remodeling in a mouse model of chronic cerebral ischemia, produced by subjecting adult male C57BL/6 mice to permanent left middle cerebral artery occlusion. Three days postoperatively, mice were randomly assigned to the environmental enrichment and standard housing groups. Mice in the standard housing group were housed and fed a standard diet. Mice in the environmental enrichment group were housed in a cage with various toys and fed a standard diet. Then, 28 days postoperatively, spatial learning and memory were tested using the Morris water maze. The expression levels of growth-associated protein 43, synaptophysin and postsynaptic density protein 95 in the hippocampus were analyzed by western blot assay. The number of synapses was evaluated by electron microscopy. In the water maze test, mice in the environmental enrichment group had a shorter escape latency, traveled markedly longer distances, spent more time in the correct quadrant (northeast zone), and had a higher frequency of crossings compared with the standard housing group. The expression levels of growth-associated protein 43, synaptophysin and postsynaptic density protein 95 were substantially upregulated in the hippocampus in the environmental enrichment group compared with the standard housing group. Furthermore, electron microscopy revealed that environmental enrichment increased the number of synapses in the hippocampal CA1 region. Collectively, these findings suggest that environmental enrichment ameliorates the spatial learning and memory impairment induced by permanent middle cerebral artery occlusion. Environmental enrichment in mice with cerebral ischemia likely promotes cognitive recovery by inducing plastic changes in synapses.

Background: Epilepsy, the world’s third most prevalent chronic brain disorder, significantly affects patients’ quality of life and increases the economic burden on families and society. Previous studies have demonstrated that FK506-binding protein 51 (FKBP51) plays a crucial role in synaptic plasticity. However, FKBP51 exhibits different functions under various physiological and pathological conditions. Our study explored the relationship between FKBP51 and epilepsy and its possible mechanism of action. We also analyzed the expression levels of postsynaptic density-95 (PSD95) and synaptophysin (SYP) in the hippocampus to examine the pathophysiology of epilepsy. Methods: A chronic epileptic kindling model was established by injecting pentylenetetrazole (PTZ) intraperitoneally, and a spontaneous seizure model was created by injecting kainic acid (KA) into the dentate gyrus using a stereotaxic apparatus. Endogenous FKBP51 expression was inhibited using adeno-associated virus (AAV)-FKBP51-Small hairpin RNAs (shRNA). The expression of FKBP51, PSD95, and SYP in the hippocampus and synaptosomes was measured through western blotting. Golgi staining and electron microscopy were used to examine spines and synaptic structures. Results: The results showed a significant increase in FKBP51 expression in the hippocampal tissue of the PTZ- and KA-induced epilepsy model groups. Inhibition of FKBP51 expression through AAV-FKBP51-shRNA resulted in a shorter latency and an elevated seizure grade score in mice. Moreover, the suppression of FKBP51 expression enhanced the expression of synaptic plasticity-related proteins, increased the density of dendritic spines, and elevated the quantity of spherical synaptic vesicles in the presynaptic membrane in the hippocampus. Conclusions: FKBP51 may serve as an endogenous protective factor in epilepsy by regulating the expression of the synaptic plasticity-related protein PSD95, the density of dendritic spines, and the number of synaptic vesicles in the hippocampal CA1.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by the formation of amyloid beta (Aβ) or tau protein aggregates, the hallmark of cognitive decline. MicroRNAs (miRNAs) have emerged as critical factors in neurogenesis and synaptic functions in the central nervous system (CNS). Recent studies have reported alterations in miRNA expression in patients with AD. However, miRNAs associated with AD varied with patient groups or experimental models, suggesting the need for a comparative study to identify miRNAs commonly dysregulated in diverse AD models. Here, we investigated the miRNAs that show dysregulated expression in two different human AD groups and mouse and cellular AD models. After selection of commonly dysregulated miRNAs in these groups, we investigated the pathophysiological significance of miR-142-5p in SH-SY5Y neuronal cells. We found that miR-142-5p was increased upon treatment with Aβ peptide 1-42 (Aβ ). Inhibition of miR-142-5p rescued the Aβ -mediated synaptic dysfunctions, as indicated by the expression of postsynaptic density protein 95 (PSD-95). Among genes with decreased expression in Aβ -treated SH-SY5Y cells, the predicted miR-142-5p target genes were significantly related with neuronal function and synapse plasticity. These findings suggest that dysregulation in miR-142-5p expression contributes the pathogenesis of AD by triggering synaptic dysfunction associated with Aβ -mediated pathophysiology.

Summary Aims Palmitoylation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPARs) subunits or their “scaffold” proteins produce opposite effects on AMPAR surface delivery. Considering AMPARs have long been identified as suitable drug targets for central nervous system (CNS) disorders, targeting palmitoylation signaling to regulate AMPAR function emerges as a novel therapeutic strategy. However, until now, much less is known about the effect of palmitoylation‐deficient state on AMPAR function. Herein, we set out to determine the effect of global de‐palmitoylation on AMPAR surface expression and its function, using a special chemical tool, N‐(tert‐Butyl) hydroxylamine (NtBuHA). Methods BS3 protein cross‐linking, Western blot, immunoprecipitation, patch clamp, and biotin switch assay. Results Bath application of NtBuHA (1.0 mM) reduced global palmitoylated proteins in the hippocampus of mice. Although NtBuHA (1.0 mM) did not affect the expression of ionotropic glutamate receptor subunits, it preferentially decreased the surface expression of AMPARs, not N‐methyl‐d‐aspartate receptors (NMDARs). Notably, NtBuHA (1.0 mM) reduces AMPAR‐mediated excitatory postsynaptic currents (mEPSCs) in the hippocampus. This effect may be largely due to the de‐palmitoylation of postsynaptic density protein 95 (PSD95) and protein kinase A‐anchoring proteins, both of which stabilized AMPAR synaptic delivery. Furthermore, we found that changing PSD95 palmitoylation by NtBuHA altered the association of PSD95 with stargazin, which interacted directly with AMPARs, but not NMDARs. Conclusion Our data suggest that the palmitoylation‐deficient state initiated by NtBuHA preferentially reduces AMPAR function, which may potentially be used for the treatment of CNS disorders, especially infantile neuronal ceroid lipofuscinosis (Batten disease).

The efficacy of stigmasterol (STG) has not been previously evaluated in post-traumatic stress disorder (PTSD) models. Mice exposed to single prolonged stress with foot shock (SPS + FS) received oral STG (25 or 50 mg/kg) for 14 days. Serum corticosterone and serotonin levels were measured, anxiety and cognition were assessed, synaptic plasticity-related proteins and genes were quantified, and neuronal nitric oxide synthase (nNOS), nitric oxide (NO) accumulation, nNOS-postsynaptic density protein 95 (PSD95), and nNOS-carboxy-terminal PDZ ligand of nNOS (CAPON) interactions were evaluated. STG significantly reduced serum corticosterone levels and increased serotonin levels altered by SPS+FS exposure. Behavioral analyses revealed attenuation of anxiety-like behavior and cognitive deficits. STG increased hippocampal synaptic plasticity-related proteins and genes and increased the number and maturation of doublecortin+ cells. Additionally, STG suppressed the PTSD-induced nNOS overactivation and NO accumulation in the hippocampus and serum, and altered nNOS-PSD95 and nNOS-CAPON associations in the hippocampus. Together, these findings provide integrated in vivo evidence suggesting that STG may influence stress-related neurobiological pathways relevant to PTSD.

Acute sleep deprivation (ASD) is prevalent in contemporary society. This study explored the mechanism of melatonin affecting cognitive dysfunction (CD) in ASD mice through the nuclear factor kappaB (NF-κB) pathway and oxidative stress. The ASD mouse model was established and treated with low-dose and high-dose melatonin, a NF-κB inhibitor PDTC, or lipopolysaccharide (LPS), with their spatial memory, spontaneous activity, and anxiety assessed. Hippocampal morphology and neuronal status were observed via HE and Nissl staining. Superoxide dismutase (SOD) activity and levels of hippocampal CA1 region postsynaptic density protein 95 (PSD95), phosphorylated (p)-p65, and p-IκB proteins; acetylcholinesterase (AChE), acetylcholine (ACh), malondialdehyde (MDA), and reactive oxygen species (ROS); and IL-4, IL-10, tumor necrosis factor [TNF]-α, and IL-1β levels were determined by western blot and ELISA kits. ASD mice exhibited reduced learning and memory abilities and spontaneous activities, loosely-arranged cells in the hippocampal CA1 region, unclear cell body boundaries, enlarged gaps, severe neuronal damage, and reduced PSD95 protein level. There were increases in AChE, p-p65, p-IκB, TNF-α, IL-1β, MDA, and ROS levels, decrements in ACh, IL-4, and IL-10 levels and SOD activity in the hippocampal CA1 region of ASD mice. Melatonin or PDTC inhibited the NF-κB pathway, down-regulated TNF-α, IL-1β, MDA, and ROS and up-regulated IL-4 and IL-10 and SOD activity in the hippocampal CA1 region of ASD mice, and improved the learning and memory abilities. LPS-induced NF-κB pathway activation partially averted melatonin's beneficial effects on ASD mice. Melatonin ameliorated ASD-induced CD in mice by modulating the NF-κB pathway and oxidative stress.

Bushen Tiansui decoction is composed of six traditional Chinese medicines: Herba Epimedii, Radix Polygoni multiflori, Plastrum testudinis, Fossilia Ossis Mastodi, Radix Polygalae, and Rhizoma Acorus tatarinowii. Because Bushen Tiansui decoction is effective against amyloid beta (Aβ) toxicity, we hypothesized that it would reduce hippocampal synaptic damage and improve cognitive function in Alzheimer's disease. To test this hypothesis, we used a previously established animal model of Alzheimer's disease, that is, microinjection of aggregated Aβ25-35 into the bilateral brain ventricles of Sprague-Dawley rats. We found that long-term (28 days) oral administration of Bushen Tiansui decoction (0.563, 1.688, and 3.375 g/mL; 4 mL/day) prevented synaptic loss in the hippocampus and increased the expression levels of synaptic proteins, including postsynaptic density protein 95, the N-methyl-D-aspartate receptor 2B subunit, and Shank1. These results suggested that Bushen Tiansui decoction can protect synapses by maintaining the expression of these synaptic proteins. Bushen Tiansui decoction also ameliorated measures reflecting spatial learning and memory deficits that were observed in the Morris water maze (i.e., increased the number of platform crossings and the amount of time spent in the target quadrant and decreased escape latency) following intraventricular injections of aggregated Aβ25-35 compared with those measures in untreated Aβ25-35-injected rats. Overall, these results provided evidence that further studies on the prevention and treatment of dementia with this traditional Chinese medicine are warranted.

Cognitive dysfunction in Alzheimer's disease is strongly associated with a reduction in synaptic plasticity, which may be induced by oxidative stress. Testosterone is beneficial in learning and memory, although the underlying protective mechanism of testosterone on cognitive performance remains unclear. This study explored the protective mechanism of a subcutaneous injection of 0.75 mg testosterone on cognitive dysfunction induced by bilateral injections of amyloid beta 1-42 oligomers into the lateral ventricles of male rats. Morris water maze test results demonstrated that testosterone treatment remarkably reduced escape latency and path length in Alzheimer's disease rat models. During probe trials, testosterone administration significantly elevated the percentage of time spent in the target quadrant and the number of platform crossings. However, flutamide, an androgen receptor antagonist, inhibited the protective effect of testosterone on cognitive performance in Alzheimer's disease rat models. Nissl staining, immunohistochemistry, western blot assay, and enzyme-linked immunosorbent assay results showed that the number of intact hippocampal pyramidal cells, the dendritic spine density in the hippocampal CA1 region, the immune response and expression level of postsynaptic density protein 95 in the hippocampus, and the activities of superoxide dismutase and glutathione peroxidase were increased with testosterone treatment. In contrast, testosterone treatment reduced malondialdehyde levels. Flutamide inhibited the effects of testosterone on all of these indicators. Our data showed that the protective effect of testosterone on cognitive dysfunction in Alzheimer's disease is mediated via androgen receptors to scavenge free radicals, thereby enhancing synaptic plasticity.

Phosphorylation-dependent peptidyl-prolyl isomerization plays key roles in cell cycle progression, the pathogenesis of cancer, and age-related neurodegeneration. Most of our knowledge about the role of phosphorylation-dependent peptidyl-prolyl isomerization and the enzyme catalyzing this reaction, the peptidyl-prolyl isomerase (Pin1), is largely limited to proteins not present in neurons. Only a handful of examples have shown that phosphorylation-dependent peptidyl-prolyl isomerization, Pin1 binding, or Pin1-mediated peptidyl-prolyl isomerization regulate proteins present at excitatory synapses. In this work, I confirm previous findings showing that Pin1 binds postsynaptic density protein-95 (PSD-95) and identify an alternative binding site in the phosphorylated N-terminus of the PSD-95. Pin1 associates its WW domain with phosphorylated threonine (T19) and serine (S25) in the N-terminus domain of PSD-95 and this association alters the local conformation of PSD-95. Most importantly, I show that proline-directed phosphorylation of the N-terminus domain of PSD-95 alters the local conformation of this region. Therefore, proline-directed phosphorylation of the N-terminus of PSD-95, Pin1 association, and peptidyl-prolyl isomerization may all play a role in excitatory synaptic function and synapse development.