Expression Of Synaptic Proteins Research Articles

Depression-like behaviors in mouse model of Sjögren's syndrome: A role of gut–microbiota–brain axis

Depression is a common psychiatric symptom in patients with Sjögren's syndrome (SS). Prevalence of depression in SS patients is significantly higher than that in the general population. Increasing evidence suggests a crucial role of gut–microbiota–brain axis in depression. In this study, we investigated whether non-obese diabetic (NOD) mice, a widely used animal model of SS, exhibit depression-like phenotypes and abnormal composition of gut microbiota. Eleven-week-old NOD mice spontaneously exhibited SS-related symptoms without pancreatic destruction. NOD mice displayed depression-like behaviors, decreased expression of synaptic proteins in the prefrontal cortex (PFC), and abnormal composition of gut microbiota. Interestingly, SS-related proinflammatory factors in the submandibular gland (SMG) and autoantibodies (anti-SSA and anti-SSB) in the plasma were correlated with the expression of synaptic proteins in the PFC or depression-like behaviors. In addition, there were correlations between the relative abundance of microbiota and SS-related symptoms (or depression-related phenotypes). These data suggest that SS-related symptoms and abnormal composition of gut microbiota may play a role in depression-like phenotypes in NOD mice through gut–microbiota–brain axis.

A Moderate Duration of Stress Promotes Behavioral Adaptation and Spatial Memory in Young C57BL/6J Mice.

Stress may serve multiple roles in cerebral functioning, ranging from a highly appropriate behavioral adaptation to a critical risk factor for susceptibility to mood disorder and cognitive impairment. It is well known that E/I (excitation/inhibition) balance is essential for maintaining brain homeostasis. However, it remains largely unknown how GABAergic and Glutamatergic neurons respond to different stressful stimuli and whether the GABAergic-Glutamatergic neuron balance is related to the transition between adaptive and maladaptive behaviors. Here, we subjected 3-month-old mice to chronic mild stress (CMS) for a period of one, two, and four weeks, respectively. The results showed that the two-week CMS procedure produced adaptive effects on behaviors and cognitive performance, with a higher number of GABAergic neuron and VGluT1-positive neurons, increasing the expressions of p-GluN2B, Reelin, and syn-PSD-95 protein in the hippocampus. In contrast, the prolonged behavioral challenge (4 week) imposes a passive coping behavioral strategy and cognitive impairment, decreased the number of GABAergic neuron, hyperactivity of VGluT1-positive neuron, increased the ratio of p-GluN2B, and decreased the expression of Reelin, syn-PSD-95 in the hippocampus. These findings suggest that a moderate duration of stress probably promotes behavioral adaptation and spatial memory by maintaining a GABAergic-Glutamatergic neuron balance and promoting the expression of synaptic plasticity-related proteins in the brain.

Neurotransmission Targets of Per- and Polyfluoroalkyl Substance Neurotoxicity: Mechanisms and Potential Implications for Adverse Neurological Outcomes.

Per- and polyfluoroalkyl substances (PFAS) are a group of persistent environmental pollutants that are ubiquitously found in the environment and virtually in all living organisms, including humans. PFAS cross the blood-brain barrier and accumulate in the brain. Thus, PFAS are a likely risk for neurotoxicity. Studies that measured PFAS levels in the brains of humans, polar bears, and rats have demonstrated that some areas of the brain accumulate greater amounts of PFAS. Moreover, in humans, there is evidence that PFAS exposure is associated with attention-deficit/hyperactivity disorder (ADHD) in children and an increased cause of death from Parkinson's disease and Alzheimer's disease in elderly populations. Given possible links to neurological disease, critical analyses of possible mechanisms of neurotoxic action are necessary to advance the field. This paper critically reviews studies that investigated potential mechanistic causes for neurotoxicity including (1) a change in neurotransmitter levels, (2) dysfunction of synaptic calcium homeostasis, and (3) alteration of synaptic and neuronal protein expression and function. We found growing evidence that PFAS exposure causes neurotoxicity through the disruption of neurotransmission, particularly the dopamine and glutamate systems, which are implicated in age-related psychiatric illnesses and neurodegenerative diseases. Evaluated research has shown there are highly reproduced increased glutamate levels in the hippocampus and catecholamine levels in the hypothalamus and decreased dopamine in the whole brain after PFAS exposure. There are significant gaps in the literature relative to the assessment of the nigrostriatal system (striatum and ventral midbrain) among other regions associated with PFAS-associated neurologic dysfunction observed in humans. In conclusion, evidence suggests that PFAS may be neurotoxic and associated with chronic and age-related psychiatric illnesses and neurodegenerative diseases. Thus, it is imperative that future mechanistic studies assess the impact of PFAS and PFAS mixtures on the mechanism of neurotransmission and the consequential functional effects.

P301S-hTau acetylates KEAP1 to trigger synaptic toxicity via inhibiting NRF2/ARE pathway: A novel mechanism underlying hTau-induced synaptic toxicities.

BackgroundHuman Tau (hTau) accumulation and synapse loss are two pathological hallmarks of tauopathies. However, whether and how hTau exerts toxic effects on synapses remain elusive.MethodsMutated hTau (P301S) was overexpressed in the N2a cell line, primary hippocampal neurons and hippocampal CA3. Western blotting and quantitative polymerase chain reaction were applied to examine the protein and mRNA levels of synaptic proteins. The protein interaction was tested by co‐immunoprecipitation and proximity ligation assays. Memory and emotion status were evaluated by a series of behavioural tests. The transcriptional activity of nuclear factor‐erythroid 2–related factor 2 (NRF2) was detected by dual luciferase reporter assay. Electrophoresis mobility shift assay and chromosome immunoprecipitation were conducted to examine the combination of NRF2 to specific anti‐oxidative response element (ARE) sequences. Neuronal morphology was analysed after Golgi staining.ResultsOverexpressing P301S decreased the protein levels of post‐synaptic density protein 93 (PSD93), PSD95 and synapsin 1 (SYN1). Simultaneously, NRF2 was decreased, whereas Kelch‐like ECH‐associated protein 1 (KEAP1) was elevated. Further, we found that NRF2 could bind to the specific AREs of DLG2, DLG4 and SYN1 genes, which encode PSD93, PSD95 and SYN1, respectively, to promote their expression. Overexpressing NRF2 ameliorated P301S‐reduced synaptic proteins and synapse. By means of acetylation at K312, P301S increased the protein level of KEAP1 via inhibiting KEAP1 degradation from ubiquitin–proteasome pathway, thereby decreasing NRF2 and reducing synapse. Blocking the P301S–KEAP1 interaction at K312 rescued the P301S‐suppressed expression of synaptic proteins and memory deficits with anxiety efficiently.ConclusionsP301S‐hTau could acetylate KEAP1 to trigger synaptic toxicity via inhibiting the NRF2/ARE pathway. These findings provide a novel and potential target for the therapeutic intervention of tauopathies.

Transcriptomic Profile Identifies Hippocampal Sgk1 as the Key Mediator of Ovarian Estrogenic Regulation on Spatial Learning and Memory and Aβ Accumulation.

Previous studies have shown that ovarian estrogens are involved in the occurrence and pathology of Alzheimer's disease (AD) through regulation on hippocampal synaptic plasticity and spatial memory; however, the underlying mechanisms have not yet been elucidated at the genomic scale. In this study, we established the postmenopausal estrogen-deficient model by ovariectomy (OVX). Then, we used high-throughput Affymetrix Clariom transcriptomics and found 143 differentially expressed genes in the hippocampus of OVX mice with the absolutefold change ≥ 1.5 and P < 0.05. GO analysis showed that the highest enrichment was seen in long-term memory. Combined with the response to steroid hormone enrichment and GeneMANIA network prediction, the serum and glucocorticoid-regulated kinase 1 gene (Sgk1) was found to be the most potent candidate for ovarian estrogenic regulation. Sgk1 overexpression viral vectors (oSgk1) were then constructed and injected into the hippocampus of OVX mice. Morris water maze test revealed that the impaired spatial learning and memory induced by OVX was rescued by Sgk1 overexpression. Additionally, the altered expression of synaptic proteins and actin remodeling proteins and changes in CA1 spine density and synapse density induced by OVX were also significantly reversed by oSgk1. Moreover, the OVX-induced increase in Aβ-producing BACE1 and Aβ and the decrease in insulin degrading enzyme were significantly reversed by oSgk1. The above results show that multiple pathways and genes are involved in ovarian estrogenic regulation of the function of the hippocampus, among which Sgk1 may be a novel potent target against estrogen-sensitive hippocampal dysfunctions, such as Aβ-initiated AD.

Brain structure and synaptic protein expression alterations after antidepressant treatment in a Wistar–Kyoto rat model of depression

BackgroundStructural MRI has demonstrated brain alterations in depression pathology and antidepressants treatment. While synaptic plasticity has been previously proposed as the potential underlying mechanism of MRI findings at a cellular and molecular scale, there is still insufficient evidence to link the MRI findings and synaptic plasticity mechanisms in depression pathology. MethodsIn this study, a Wistar-Kyoto (WKY) depression rat model was treated with antidepressants (citalopram or Jie-Yu Pills) and tested in a series of behavioral tests and a 7.0 MRI scanner. We then measured dendritic spine density within altered brain regions. We also examined expression of synaptic marker proteins (PSD-95 and SYP). ResultsWKY rats exhibited depression-like behaviors in the sucrose preference test (SPT) and forced swim test (FST), and anxiety-like behaviors in the open field test (OFT). Both antidepressants reversed behavioral changes in SPT and OFT but not in FST. We found a correlation between SPT performance and brain volumes as detected by MRI. All structural changes were consistent with alterations of the corpus callosum (white matter), dendritic spine density, as well as PSD95 and SYP expression at different levels. Two antidepressants similarly reversed these macro- and micro-changes. LimitationsThe single dose of antidepressants was the major limitation of this study. Further studies should focus on the white matter microstructure changes and myelin-related protein alterations, in addition to comparing the effects of ketamine. ConclusionTranslational evidence links structural MRI changes and synaptic plasticity alterations, which promote our understanding of SPT mechanisms and antidepressant response in WKY rats.

All-trans Retinoic Acid has Limited Therapeutic Effects on Cognition and Hippocampal Protein Expression After Controlled Cortical Impact

Traumatic brain injury (TBI) is known to impair synaptic function, and subsequently contribute to observed cognitive deficits. Retinoic Acid (RA) signaling modulates expression of synaptic plasticity proteins and is involved in hippocampal learning and memory. All trans-retinoic acid (ATRA), a metabolite of Vitamin A, has been identified as a potential pharmacotherapeutic for other neurological disorders due to this role. This study conducted an ATRA dose response to determine its therapeutic effects on cognitive behaviors and expression of hippocampal markers of synaptic plasticity and RA signaling proteins after experimental TBI. Under isoflurane anesthesia, adult male Sprague Dawley rats received either controlled cortical impact (CCI, 2.5 mm deformation, 4 m/s) or control surgery. Animals received daily intraperitoneal injection of 0.5, 1, 5, or 10 mg/kg of ATRA or vehicle for 2 weeks. Animals underwent motor and spatial learning and memory testing. Hippocampal expression of synaptic plasticity proteins neurogranin (Ng), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 sub-unit, as well as RA signaling proteins STRA6, ADLH1a1, CYP26A1 and CYP26B1 were evaluated by western blot at 2-weeks post-injury. ATRA treatment significantly recovered Ng synaptic protein expression, while having no effect on motor performance, spatial learning, and memory, and GluA1 expression after TBI. RA signaling protein expression is unchanged 2 weeks after TBI.Overall, ATRA administration after TBI showed limited therapeutic benefits compared to the vehicle.

The epigenetic reader PHF21B modulates murine social memory and synaptic plasticity-related genes.

Synaptic dysfunction is a manifestation of several neurobehavioral and neurological disorders. A major therapeutic challenge lies in uncovering the upstream regulatory factors controlling synaptic processes. Plant homeodomain (PHD) finger proteins are epigenetic readers whose dysfunctions are implicated in neurological disorders. However, the molecular mechanisms linking PHD protein deficits to disease remain unclear. Here, we generated a PHD finger protein 21B–depleted (Phf21b-depleted) mutant CRISPR mouse model (hereafter called Phf21bΔ4/Δ4) to examine Phf21b’s roles in the brain. Phf21bΔ4/Δ4 animals exhibited impaired social memory. In addition, reduced expression of synaptic proteins and impaired long-term potentiation were observed in the Phf21bΔ4/Δ4 hippocampi. Transcriptome profiling revealed differential expression of genes involved in synaptic plasticity processes. Furthermore, we characterized a potentially novel interaction of PHF21B with histone H3 trimethylated lysine 36 (H3K36me3), a histone modification associated with transcriptional activation, and the transcriptional factor CREB. These results establish PHF21B as an important upstream regulator of synaptic plasticity–related genes and a candidate therapeutic target for neurobehavioral dysfunction in mice, with potential applications in human neurological and psychiatric disorders.

Contralateral synaptic changes following severe unilateral brain injury

The brain is highly integrated and thus unilateral injury can impact the contralateral hemisphere. However, further research is needed to clarify the changes in the response of the contralateral homotopic area to ipsilateral injury. We hypothesized that severe unilateral brain injury would be accompanied by contralateral synaptic changes that are related to functional recovery. To test this, we divided rats into sham and experimental groups. In the experimental group, we performed right motor cortex resection. These rats were further divided into three subgroups according to post-injury time: 7 days, 14 days, and 30 days post-injury. Rats in each group were evaluated using a beam walking test to quantify the recovery of motor function, and all rats received an injection of adeno-associated virus-containing green fluorescent protein (GFP). Finally, we conducted morphological and histological analyses to identify synaptic changes. Over time, the behavior of the rats that underwent right motor cortex resection recovered. Furthermore, in contrast to the sham group, the experimental groups exhibited an increase in the spine density and expression of synaptic proteins in layer V of the contralateral motor cortex, which was consistent with the GFP-labeled neurons. Moreover, more immature spines were observed 7 days post-injury. Notably, spine morphology matured from 7 to 30 days, and the increase in Synapsin-1 intensity in layer V peaked 14 days after the resection, whereas PSD-95 intensity continued to increase until day 30. Our findings suggested that following motor function recovery from unilateral brain injury, spine morphology and synaptic proteins change dynamically in the contralateral hemisphere.

Lactobacillus plantarum Combined with Galactooligosaccharides Supplement: A Neuroprotective Regimen Against Neurodegeneration and Memory Impairment by Regulating Short-Chain Fatty Acids and the c-Jun N-Terminal Kinase Signaling Pathway in Mice.

Probiotics and prebiotics have received attention in alleviating neurodegenerative diseases. Lactobacillus plantarum (L. plantarum) 69-2 was combined with galactooligosaccharides (GOS) and supplemented in a d-galactose (d-gal)-induced neurodegeneration and memory impairment mice model to explore its effects on the brain and the regulation of short-chain fatty acids. The results showed that the L. plantarum-GOS supplementation inhibited d-gal-induced oxidative stress and increased the brain's nuclear factor erythroid 2-related factor 2 (Nrf2) levels. Butyrate, a metabolite of the gut microbiota regulated by L. plantarum combined with GOS, inhibits p-JNK expression, downregulates pro-apoptotic proteins expression and the activation of inflammatory mediators, and upregulates synaptic protein expression. This might be a potential mechanism for L. plantarum 69-2 combined with GOS supplementation to alleviate d-gal-induced neurodegeneration and memory impairment. This study sheds new light on the development of aging-related neuroprotective dietary supplements based on the gut-brain axis.

Phenylethanoid Glycosides of Cistanche Improve Learning and Memory Disorders in APP/PS1 Mice by Regulating Glial Cell Activation and Inhibiting TLR4/NF-κB Signaling Pathway.

Phenylethanoid Glycosides of Cistanche (PhGs) have a certain curative effect on AD animal model, Echinacea (ECH) and verbascoside (ACT), as the quality control standard of Cistanche deserticola Y. C. Ma and the main representative compounds of PhGs have been proved to have neuroprotective effects, but the specific mechanism needs to be further explored. This study explored the mechanisms of PhGs, ECH, and ACT in the treatment of Alzheimer's disease (AD) from the perspectives of glial cell activation, TLR4/NF-κB signaling pathway, and synaptic protein expression. We used APP/PS1 mice as AD models. After treatment with PhGs, ECH, and ACT, the learning and memory abilities of APP/PS1 mice were enhanced, and the pathological changes in brain tissue were alleviated. The expression of pro-inflammatory M1 microglia markers (CD11b, iNOS, and IL-1β) was decreased; the expression of M2 microglia markers (Arg-1 and TGF-β1) was increased, which promoted the transformation of microglia from M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype. In addition, PhGs, ECH, and ACT could down-regulate the expression of proteins related to the TLR4/NF-κB signaling pathway and up-regulate the expression of synaptic proteins. The results indicated that PhGs, ECH, and ACT played a neuroprotective role by regulating the activation of glial cells and inhibiting the TLR4/NF-κB inflammatory pathway, and improving the expression levels of synapse-related proteins.

Repetitive transcranial magnetic stimulation promotes neurological functional recovery in rats with traumatic brain injury by upregulating synaptic plasticity-related proteins.

Studies have shown that repetitive transcranial magnetic stimulation (rTMS) can enhance synaptic plasticity and improve neurological dysfunction. However, the mechanism through which rTMS can improve moderate traumatic brain injury remains poorly understood. In this study, we established rat models of moderate traumatic brain injury using Feeney's weight-dropping method and treated them using rTMS. To help determine the mechanism of action, we measured levels of several important brain activity-related proteins and their mRNA. On the injured side of the brain, we found that rTMS increased the protein levels and mRNA expression of brain-derived neurotrophic factor, tropomyosin receptor kinase B, N-methyl-D-aspartic acid receptor 1, and phosphorylated cAMP response element binding protein, which are closely associated with the occurrence of long-term potentiation. rTMS also partially reversed the loss of synaptophysin after injury and promoted the remodeling of synaptic ultrastructure. These findings suggest that upregulation of synaptic plasticity-related protein expression is the mechanism through which rTMS promotes neurological function recovery after moderate traumatic brain injury.

A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway.

As a neurodegenerative disease, Alzheimer’s disease (AD) seriously affects the health of older people. Changes in synapses occur first over the course of the disease, perhaps even before the formation of Aβ plaques. Histone deacetylase (HDAC) mediates the damage of Aβ oligomers to dendritic spines. Therefore, we examined the relationship between HDAC activity and synaptic defects using an HDAC inhibitor (HDACI), BG45, in the human neuroblastoma SH-SY5Y cell line with stable overexpression of Swedish mutant APP (APPsw) and in APP/PS1 transgenic mice during this study. The cells were treated with 15 μM BG45 and the APP/PS1 mice were treated with 30 mg/kg BG45. We detected the levels of synapse-related proteins, HDACs, tau phosphorylation, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors using Western blotting and immunohistochemistry. We also measured the expression of cytoskeletal proteins in the cell model. The mRNA levels of the glutamate ion receptor alginate subunit 2 (GRIK2), sodium voltage-gated channel beta subunit (SCN3B), synaptophysin (SYP), Grm2 (the gene encoding glutamate receptor subunit 2 (GluR2)), Grid2IP, glutamate receptor interacting protein 1 (GRIP1), and GRIP2 were detected to explore the effects of the HDACI on regulating the expression of synaptic proteins and AMPA receptors. According to our studies, the expressions of HDAC1, HDAC2, and HDAC3 were increased, which were accompanied by the downregulation of the synapse-related proteins SYP, postsynaptic dendritic protein (PSD-95), and spinophilin as early as 24 h after transfection with the APPsw gene. BG45 upregulated the expression of synapse-related proteins and repaired cytoskeletal damage. In vivo, BG45 alleviated the apoptosis-mediated loss of hippocampal neurons, upregulated synapse-related proteins, reduced Aβ deposition and phosphorylation of tau, and increased the levels of the synapse-related genes GRIK2, SCN3B, SYP, Grm2, and Grid2IP. BG45 increased the expression of the AMPA receptor subunits GluA1, GluA2, and GluA3 on APPsw-transfected cells and increased GRIP1 and GRIP2 expression and AMPA receptor phosphorylation in vivo. Based on these results, HDACs are involved in the early process of synaptic defects in AD models, and BG45 may rescue synaptic damage and the loss of hippocampal neurons by specifically inhibiting HDAC1, HDAC2, and HDAC3, thereby modulating AMPA receptor transduction, increasing synapse-related gene expression, and finally enhancing the function of excitatory synapses. BG45 may be considered a potential drug for the treatment of early AD in further studies.

Cattle Encephalon Glycoside and Ignotin Ameliorate Palmitoylation of PSD-95 and Enhance Expression of Synaptic Proteins in the Frontal Cortex of a APPswe/PS1dE9 Mouse Model of Alzheimer's Disease.

Synaptic abnormalities in synaptic proteins are the initial hallmarks of Alzheimer's disease (AD). The higher level of palmitoylation of synaptic proteins was closely associated with amyloid-β (Aβ) in AD. Cattle encephalon glycoside and ignotin (CEGI) have been shown to act as multitarget neurotrophic agents in APPswe/PS1dE9 (APP/PS1) transgenic AD mice. However, it is not clear whether CEGI can influence Aβ deposition or whether it does so by the regulation of protein palmitoylation and expression of synaptic proteins in transgenic AD mice. In this study, we investigated the roles of CEGI in modulating postsynaptic density protein 95 (PSD-95) palmitoylation, Aβ pathologies, and expression of synaptic-associated proteins in APP/PS1 mice. Five-month-old APP/PS1 mice were treated intraperitoneally with 6.6 mL/kg of CEGI for 6 weeks. At the end of the treatment period, APP/PS1 mice were subjected to Morris water maze to test their cognitive functions. Acyl-biotinyl exchange (ABE) for PSD-95 palmitoylation, immunofluorescent staining for expression of PSD-95, N-methyl-D-aspartic acid receptor subunit 2B (NR2B), and synaptotagmin 1 (SYT1) were assessed in mouse brain sections. CEGI treatment in APP/PS1 mice significantly reduced Aβ deposition, relieved memory deficits, and decreased PSD-95 palmitoylation while markedly increasing the expression of PSD-95, NR2B, and SYT1 in the frontal cortex. There was a significant correlation between Aβ expression and PSD-95 palmitoylation in APP/PS1 mice. Our findings demonstrate that CEGI improved AD-like neuropathology, possibly by inhibiting PSD-95 palmitoylation, improving learning memory, and enhancing expression of synaptic-associated proteins, representing a potential therapy for AD treatment.

Roflumilast, a Phosphodiesterase-4 Inhibitor, Ameliorates Sleep Deprivation-Induced Cognitive Dysfunction in C57BL/6J Mice

Sleep deprivation (SD) interferes with long-term memory and cognitive functions by overactivation of phosphodiesterase (PDEs) enzymes. PDE4, a nonredundant regulator of the cyclic nucleotides (cAMP), is densely expressed in the hippocampus and is involved in learning and memory processes. In the present study, we investigated the effects of Roflumilast (ROF), a PDE4B inhibitor, on sleep deprivation-induced cognitive dysfunction in a mouse model. Memory assessment was performed using a novel object recognition task, and the hippocampal cAMP level was estimated by the ELISA method. The alterations in the expressions of PDE4B, amyloid-β (Aβ), CREB, BDNF, and synaptic proteins (Synapsin I, SAP 97, PSD 95) were assessed to gain insights into the possible mechanisms of action of ROF using the Western blot technique. Results show that ROF reversed SD-induced cognitive decline in mice. ROF downregulated PDE4B and Aβ expressions in the brain. Additionally, ROF improved the cAMP level and the protein expressions of synapsin I, SAP 97, and PSD 95 in the hippocampal region of SD mice. Taken together, these results suggest that ROF can suppress the deleterious effects of SD-induced cognitive dysfunction via the PDE4B-mediated cAMP/CREB/BDNF signaling cascade.

Binge-like Prenatal Ethanol Exposure Causes Impaired Cellular Differentiation in the Embryonic Forebrain and Synaptic and Behavioral Defects in Adult Mice.

An embryo’s in-utero exposure to ethanol due to a mother’s alcohol drinking results in a range of deficits in the child that are collectively termed fetal alcohol spectrum disorders (FASDs). Prenatal ethanol exposure is one of the leading causes of preventable intellectual disability. Its neurobehavioral underpinnings warrant systematic research. We investigated the immediate effects on embryos of acute prenatal ethanol exposure during gestational days (GDs) and the influence of such exposure on persistent neurobehavioral deficits in adult offspring. We administered pregnant C57BL/6J mice with ethanol (1.75 g/kg) (GDE) or saline (GDS) intraperitoneally (i.p.) at 0 h and again at 2 h intervals on GD 8 and GD 12. Subsequently, we assessed apoptosis, differentiation, and signaling events in embryo forebrains (E13.5; GD13.5). Long-lasting effects of GDE were evaluated via a behavioral test battery. We also determined the long-term potentiation and synaptic plasticity-related protein expression in adult hippocampal tissue. GDE caused apoptosis, inhibited differentiation, and reduced pERK and pCREB signaling and the expression of transcription factors Pax6 and Lhx2. GDE caused persistent spatial and social investigation memory deficits compared with saline controls, regardless of sex. Interestingly, GDE adult mice exhibited enhanced repetitive and anxiety-like behavior, irrespective of sex. GDE reduced synaptic plasticity-related protein expression and caused hippocampal synaptic plasticity (LTP and LTD) deficits in adult offspring. These findings demonstrate that binge-like ethanol exposure at the GD8 and GD12 developmental stages causes defects in pERK–pCREB signaling and reduces the expression of Pax6 and Lhx2, leading to impaired cellular differentiation during the embryonic stage. In the adult stage, binge-like ethanol exposure caused persistent synaptic and behavioral abnormalities in adult mice. Furthermore, the findings suggest that combining ethanol exposure at two sensitive stages (GD8 and GD12) causes deficits in synaptic plasticity-associated proteins (Arc, Egr1, Fgf1, GluR1, and GluN1), leading to persistent FASD-like neurobehavioral deficits in mice.

Glutamatergic transmission and receptor expression in the synucleinopathy h-α-synL62 mouse model: Effects of hydromethylthionine

The accumulation of alpha-synuclein (α-Syn) into Lewy bodies in cortical and subcortical regions has been linked to the pathogenesis of synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While there is a strong link between synuclein aggregates and the reduction in dopamine function in the emergence of PD, less is known about the consequences of α-Syn accumulation in glutamatergic neurons and how this could be exploited as a therapeutic target. Transgenic h-α-synL62 (L62) mice, in which synuclein aggregation is achieved through the expression of full-length human α-Syn fused with a signal sequence peptide, were used to characterise glutamatergic transmission using a combination of behavioural, immunoblotting, and histopathological approaches. The protein aggregation inhibitor hydromethylthionine mesylate (HMTM) alone, or in combination with the glutamatergic compounds 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine hydrochloride (MTEP) and memantine, was used to target α-Syn aggregation. We show that accumulation of α-Syn aggregates in glutamatergic synapses affected synaptic protein expression including metabotropic glutamate receptor 5 (mGLUR5) levels and ratio of N-methyl-d-aspartate (NMDA) receptor subunits GluN1/GluN2A. The ratio of NMDA receptor subunits and levels of mGLUR5 were both normalised by HMTM in L62 mice. These alterations, however, did not affect glutamate release in synaptosomes derived from L62 mice or behavioural endpoints following pharmacological manipulations of glutamate functions. Our results confirm that HMTM acts in the L62 mouse model of PD as an inhibitor of pathological aggregation of synuclein and show that HMTM treatment normalises both the ratio of NMDA receptor subunits and mGLUR5 levels. These findings support the potential utility of HMTM as a disease-modifying treatment for PD aiming to reduce synuclein aggregation pathology.

7,8-Dihydroxycoumarin Alleviates Synaptic Loss by Activated PI3K-Akt-CREB-BDNF Signaling in Alzheimer's Disease Model Mice.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is clinically characterized by the impairment of memory and cognition. Accumulation of β-amyloid (Aβ) in the brain is considered as a key process in the development of AD because it impairs the synapses’ function to impair memory formation. Recent research studies have indicated that a group of edible plant-derived Thymelaeaceae compounds known as coumarin may exert particularly powerful actions on alleviating learning and memory impairment. 7,8-Dithydroxycoumarin (7,8-DHC), a bioactive component of coumarin derived from Thymelaeaceae, showed its function in neuroprotection before. In this study, we found that 7,8-DHC was able to mitigate Aβ accumulation via reducing the level of BACE1 and increasing the level of ADAM17 and ADAM10. More importantly, we found that 7,8-DHC could mitigate memory impairment, promote the dendrite branch density, and increase synaptic protein expression via activating PI3K-Akt-CREB-BDNF signaling. Hence, these results suggested that 7,8-DHC represented a novel bioactive therapeutic agent in mitigating Aβ deposition and synaptic loss in the process of treating AD.

Fecal microbiota transplantation from patients with rheumatoid arthritis causes depression-like behaviors in mice through abnormal T cells activation

Depression is common in patients with rheumatoid arthritis (RA); however, the precise mechanisms underlying a link between depression and RA remain unclear. Accumulating evidence suggests the role of gut–microbiota–brain axis in depression. In this study, we investigated whether collagen-induced arthritis (CIA) mice produce depression-like behaviors and abnormal composition of gut microbiota. Furthermore, we investigated whether fecal microbiota transplantation (FMT) from RA patients causes depression-like phenotypes in antibiotic cocktail (ABX)-treated mice. CIA mice displayed depression-like behaviors, increased blood levels of pro-inflammatory cytokine interleukin-6 (IL-6), decreased expression of synaptic proteins in the prefrontal cortex (PFC), and abnormal composition of gut microbiota. Furthermore, FMT from RA patients caused depression-like phenotypes, alterations of gut microbiota composition, increased levels of IL-6 and tumor necrosis factor-α (TNF-α), and downregulation of synaptic proteins in the PFC compared to FMT from healthy controls. There were correlations between relative abundance of microbiota and plasma cytokines, expression of synaptic proteins in the PFC or depression-like behaviors. Interestingly, FMT from RA patients induced T cells differentiation in Peyer’s patches and spleen. Reduced percentage of Treg cells with an increase of Th1/Th2 index was observed in the mice after FMT from RA patients. These findings suggest that CIA mice exhibit depression-like behaviors, systemic inflammation, and abnormal composition of gut microbiota, and that FMT from RA patients produces depression-like behaviors in ABX-treated mice via T cells differentiation. Therefore, abnormalities in gut microbiota in RA patients may contribute to depression via gut–microbiota–brain axis.

Ppp4r3a deficiency leads to depression-like behaviors in mice by modulating the synthesis of synaptic proteins.

ABSTRACTChronic stress is one of the main risk factors for the onset of major depressive disorder. Chronic unpredictable mild stress results in reduced expression of synaptic proteins and depression-like behaviors in rodent models. However, the upstream molecule that senses the demand for synaptic proteins and initiates their synthesis under chronic stress remains unknown. In this study, chronic unpredictable mild stress reduced the expression of PPP4R3A in the prefrontal cortex and hippocampus in mice. Selective knockout of Ppp4r3a in the cortex and hippocampus mimicked the depression- and anxiety-like behavioral effects of chronic stress in mice. Notably, Ppp4r3a deficiency led to downregulated mTORC1 signaling, which resulted in reduced synthesis of synaptic proteins and impaired synaptic functions. By contrast, overexpression of Ppp4r3a in the cortex and hippocampus protected against behavioral and synaptic deficits induced by chronic stress in a PPP4R3A–mTORC1-dependent manner. Rapamycin treatment of Ppp4r3a-overexpressing neurons blocked the regulatory effect of Ppp4r3a on the synthesis of synaptic proteins by directly inhibiting mTORC1. Overall, our results reveal a regulatory role of Ppp4r3a in driving synaptic protein synthesis in chronic stress.