Impaired Synaptic Plasticity Research Articles

Impaired Synaptic Plasticity in the mPFC and Anxiety-Like Behaviour in Rats Following Repeated Nitrous Oxide Exposure

Impaired Synaptic Plasticity in the mPFC and Anxiety-Like Behaviour in Rats Following Repeated Nitrous Oxide Exposure

Activation of SIRT-1 Pathway by Nanoceria Sheds Light on Its Ameliorative Effect on Doxorubicin-Induced Cognitive Impairment (Chemobrain): Restraining Its Neuroinflammation, Synaptic Dysplasticity and Apoptosis.

Chemo fog is one of the most serious health concerns encountered by cancer survivors receiving doxorubicin (DOX)-based chemotherapy. Oxidative stress, neuroinflammation, apoptosis and impairment of synaptic plasticity are regarded as the key factors implicated in DOX-induced cognitive impairment. This research aimed to assess the possible neuroprotective effect of cerium oxide nanoparticles (CeNPs) against DOX-induced neurotoxicity. Forty-eight rats were divided into four groups (12 rats/group): control group, CeNPs group (received oral CeNPs solution (35 mg/kg) daily for 4 weeks), and DOX group (were administered DOX intraperitoneally (2 mg/kg, once/week for 4 weeks)) and DOX+ CeNPs group. The findings revealed that CeNPs mitigated behavioral alterations in DOX-induced cognitive deficit. Additionally, CeNPs alleviated the histopathological abnormalities in hippocampus and ameliorated DOX-induced neuroinflammation by downregulating the expression of NF-κB, TNF-α, IL-1β and IL6. In addition, CeNPs antagonized the apoptosis through reducing the protein expression of cytochrome c and caspase 3. In addition, it stimulated the antioxidant defense, as indicated by upregulating the expression of the Nrf2, HO-1 and PGC-1α genes. CeNPs improved synaptic plasticity via acting on the BDNF. These actions were related through the modification of SIRT-1 expression. Based on the aforementioned results, CeNPs antagonized the doxorubicin-induced neurodegeneration by its antioxidant, anti-inflammatory and antiapoptotic effects, alongside its SIRT-1 mediated mechanisms.

Sleep deprivation leads to further impairment of hippocampal synaptic plasticity by suppressing melatonin secretion in the pineal gland of chronically unpredictable stress rats

There has been ample research showing that insomnia is a potential trigger of depression as well as a symptom of depression. These two factors contribute to behavioural problems and are closely related to the plasticity of hippocampal synapses. Although depression and insomnia impair hippocampal synaptic plasticity, the mechanism by which this happens remains a mystery. This study aimed to investigate the pathogenesis of insomnia comorbidity in depression and the regulatory effect of venlafaxine combined with melatonin on hippocampal synaptic plasticity in chronic unpredictable mild stress (CUMS) with sleep deprivation (SD) rats. Thus, rats were subjected to 14 days of chronic mild unpredictable stress, gradually acclimated to sleep deprivation on days 12–14. Followed by 21 consecutive days of sleep deprivation, 18 h per day, with daily gavage of venlafaxine (13.5 mg/kg) + melatonin (72 mg/kg) on days 15–36. Venlafaxine + melatonin treatment improves depression-like behaviour, pentobarbital sodium experimental sleep latency, and sleep duration in CUMS +SD rats. In addition to improving depressive-like behaviors, sleep deprivation also upregulates the expression of caspase-specific cysteine protein 3 (Caspase 3) in the pineal glial cells of chronic mild rats, as well as in hippocampal microglia. Expression of ionic calcium-binding adaptor 1 (iba-1), downregulates the secretion of several synaptic plasticity-related proteins, notably cAMP response element binding protein (CREB), glial cell line-derived neurotrophic factor (GDNF), and the synaptic scaffolding protein Spinophiline (Spinophiline). Hematoxylin-eosin staining showed that the structure of the pineal gland and hippocampus was damaged, and Golgi staining showed that the dendrites and spines in the DG area of the hippocampus were destroyed, vaguely aggregated or even disappeared, and the connection network could not be established. Western blot analysis further revealed a positive correlation between low melatonin levels and reduced Spinophiline protein. Interestingly, venlafaxine + melatonin reversed these events by promoting hippocampal synaptic plasticity by regulating melatonin secretion from the pineal gland. Therefore, it exerted an antidepressant effect in sleep deprivation combined with CUMS model rats. Overall, the results of this study suggest that the pathophysiology of depressive insomnia comorbidity is mediated by impaired pineal melatonin secretion and impaired hippocampal synaptic plasticity. In addition, these responses are associated with melatonin secretion from the pineal gland.

Brain-immune interaction mechanisms: Implications for cognitive dysfunction in psychiatric disorders.

ObjectivesCognitive dysfunction has been identified as a major symptom of a series of psychiatric disorders. Multidisciplinary studies have shown that cognitive dysfunction is monitored by a two‐way interaction between the neural and immune systems. However, the specific mechanisms of cognitive dysfunction in immune response and brain immune remain unclear.Materials and methodsIn this review, we summarized the relevant research to uncover our comprehension of the brain–immune interaction mechanisms underlying cognitive decline.ResultsThe pathophysiological mechanisms of brain‐immune interactions in psychiatric‐based cognitive dysfunction involve several specific immune molecules and their associated signaling pathways, impairments in neural and synaptic plasticity, and the potential neuro‐immunological mechanism of stress.ConclusionsTherefore, this review may provide a better theoretical basis for integrative therapeutic considerations for psychiatric disorders associated with cognitive dysfunction.

Malfunction of astrocyte and cholinergic input is involved in postoperative impairment of hippocampal synaptic plasticity and cognitive function

Postoperative delirium (POD) occurs in a few days after major surgery under general anesthesia and may cause serious health problems. However, effective intervention and treatment remain unavailable because the underlying mechanisms have far been elucidated. In the present study, we explored the role of the malfunctioned astrocytes in POD. Our results showed that mice with tibia fracture displayed spatial and temporal memory impairments, reduced LTP, and activated astrocytes in the hippocampus in early postoperative stage. Using electrophysiological and Ca2+ imaging techniques in hippocampal slices, we demonstrated the malfunctions of astrocytes in surgery mice: depolarized resting membrane potential, higher membrane conductance and capacitance, and attenuated Ca2+ elevation in response to external stimulation. The degraded calcium signaling in hippocampal astrocytes in surgery mice was restored by correcting the diminution of acetylcholine release with galantamine. Furthermore, pharmacologically blocking astrocyte activation with fluorocitrate and enhancing cholinergic inputs with galantamine normalized hippocampal LTP in surgery mice. Finally, inhibition of astrocyte activation with fluorocitrate in the hippocampus improved cognitive function in surgery mice. Therefore, the prevention of astrocyte activation may be a valuable strategy for the intervention of cognitive dysfunction in POD, and acetylcholine receptors may be valid drug targets for this purpose.

Modulation of synaptic plasticity, motor unit physiology, and TDP-43 pathology by CHCHD10

Mutations in CHCHD10, a gene coding for a mitochondrial intermembrane space protein, are associated with Frontotemporal dementia (FTD)-Amyotrophic lateral sclerosis (ALS) spectrum disorders, which are pathologically characterized by cytoplasmic inclusions containing TDP-43. FTD/ALS-linked CHCHD10 mutations and TDP-43 inclusions similarly induce mitochondrial defects in respiration, fusion/fission, mtDNA stability, and cristae structure, while sizeable amounts of cytoplasmic TDP-43 aggregates are found in mitochondria. However, the mechanistic link between CHCHD10 and TDP-43 pathogenesis remains unclear. In this study, we present immunohistochemical and biochemical evidence demonstrating that insoluble CHCHD10 aggregates accumulate and colocalize with phospho-TDP-43 inclusions in brains of FTLD-TDP and AD patients, and that insoluble CHCHD10 levels tightly correlate with insoluble TDP-43 levels in control and FTLD-TDP brains. In an experimental exploration of this pathological phenotype, transgenic mice neuronally expressing FTD/ALS-linked CHCHD10R15L or CHCHDS59L mutations but not CHCHD10WT transgenic mice exhibit significantly increased CHCHD10 aggregation and phospho-TDP-43 pathology, which often colocalize within the same inclusions. Such pathologies are reflected in poor functional outcomes in long-term synaptic plasticity, motor unit physiology, and behavior in CHCHD10R15L and CHCHDS59L transgenic mice. In contrast, expression of CHCHD10WT in hTDP-43 transgenic mice (TAR4;CHCHD10WT) significantly mitigates phospho-TDP-43 pathology and rescues TDP-43-induced impairments in synaptic integrity and long-term synaptic plasticity. In isolated mitochondria, the S59L mutation induces the aggregation of resident CHCHD10S59L protein as well as the aggregation and slower turnover of recombinant TDP-43 imported into mitochondria. Likewise, in an in vitro cell-free system, the S59L mutation induces the aggregation of CHCHD10S59L protein while simultaneously enhancing the aggregation of recombinant TDP-43, as evidenced by filter trap assays and atomic force microscopy. In contrast, recombinant CHCHD10WT inhibits the growth of TDP-43 aggregates. These results in human brains, transgenic mice, and in vitro systems substantiate the role of wild type and mutant CHCHD10 in modulating mitochondrial CHCHD10 and TDP-43 pathogenesis together with associated phenotypes in long-term synaptic plasticity and motor unit physiology in mice and humans.

FAM69C, a kinase critical for synaptic function and memory, is defective in neurodegenerative dementia.

Synapse loss and memory decline are the primary features of neurodegenerative dementia. However, the molecular underpinnings that drive memory loss remain largely unknown. Here, we report that FAM69C is a kinase critically involved in neurodegenerative dementia. Biochemical analyses uncover that FAM69C is a serine/threonine kinase. We generate the Fam69c knockout mice and show by single-cell RNA sequencing that FAM69C deficiency drives cell-type-specific transcriptional changes relevant to synapse dysfunction. Electrophysiological, morphological, and behavioral experiments demonstrate impairments in synaptic plasticity, dendritic spine density, and memory in Fam69c knockout mice, as well as stress-induced neuronal death. Phosphoproteomic characterizations reveal that FAM69C substrates are involved in synaptic structure and function. Finally, reduced levels of FAM69C are found in postmortem brains of Alzheimer's disease patients. Our study demonstrates that FAM69C is a protective regulator of memory and suggests FAM69C as a potential therapeutic target for memory loss in neurodegenerative dementia.

P-Coumaric acid mitigates passive avoidance memory and hippocampal synaptic plasticity impairments in aluminum chloride-induced Alzheimer's disease rat model

The present study was designed to determine the effects of p-coumaric acid (p-CA), a phenolic compound, on passive avoidance memory function and hippocampal long-term potentiation (LTP) in an Alzheimer's disease (AD) rat model induced by aluminum chloride (AlCl3). p-CA (100 mg/kg; P.O.) was administered concomitantly with AlCl3 (100 mg/kg; P.O.) for 42 consecutive days. Results of this study revealed an attenuation of memory capacity, which was accompanied by a reduction in both components of LTP (field excitatory postsynaptic potentials slope and population spike amplitude) and an increase in amyloid-beta (Aβ) plaques production in the AlCl3-exposed rats. Intriguingly, treatment with p-CA improved passive avoidance memory dysfunction, ameliorated hippocampal LTP impairment, and hindered Aβ plaque accumulation in the hippocampal dentate gyrus of AlCl3-treated rats. This data provides evidence that p-CA improves AlCl3-induced passive avoidance memory decline, which may be partly related to amelioration of synaptic dysfunction and suppression of Aβ plaque formation.

DFO treatment protects against depression-like behaviors and cognitive impairment in CUMS mice

Depression has several negative effects on emotion as well as learning and memory abilities. Previous studies showed that depression could exacerbate inflammation, which in turn further aggravated depression. Deferoxamine (DFO) is a chelating agent binding iron and aluminium, and is clinically applied to treat acute ion poisoning and hemochromatosis. Researches showed that it could reduce inflammation via increasing the expression of hypoxia-inducible factor-1alpha (HIF-1α). Here, we established a chronic unpredictable mild stress (CUMS) model to investigate whether DFO exerted a neuroprotective function in depression. The results demonstrated that CUMS (4 weeks) effectively induced depression-like behaviors in mice based on sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), open field test (OFT), and elevated plus-maze test (EPT). It also brought cognitive deficits based on Morris water maze (MWM) test and the impairment of synaptic plasticity based on in vivo electrophysiological recordings. Additionally, CUMS exposure significantly decreased the expression of hippocampal synapse related proteins and the spine density of neurons in the DG region, accompanied by increasing the expression of hippocampal inflammatory cytokines, and promoted the activation of microglia in the hippocampus. The expression of HIF-1α was down-regulated as expected. However, DFO distinctly reversed the CUMS-induced impairments. The mechanism is associated with the DFO inhibition of inflammation by upregulating HIF-1 expression, thereby alleviating a series of pathology changes. Together, these findings suggest that DFO likely plays a protective role in cognitive impairments and synaptic plasticity deficits resulting from depression.

Variable Phenotypes of ZC4H2-Associated Rare Disease in Six Patients

PurposeWieacker-Wolff syndrome is a rare disease caused by X-linked zinc finger C4H2-type containing (ZC4H2) mutations. It is characterized by arthrogryposis multiplex congenita (AMC) and intellectual disability (ID), including impairment of central and peripheral synaptic plasticity. Currently, it is named “ZC4H2-associated rare disease” (ZARD) due to various clinical features other than AMC and ID. Here, we report six cases of ZARD, and describe their variable clinical phenotypes.MethodsWe analyzed the detailed clinical features and genotypes of six patients diagnosed by whole-exome sequencing or a chromosomal microarray.ResultsIn the four male patients, hemizygous mutations were found (c. 245A>C in two patients, c. 610C>A in one patient, and c.637C>T in one patient), and all variants were identified by Sanger sequencing. In the female patients, a 1.16-Mb deletion in Xq11.2, including ZC4H2, was identified by chromosomal microarray. All patients had heterogeneous phenotypes with variable severities. Motor delay was observed in all patients, four of whom could not walk independently. Other neurological features included ID, spasticity, and seizures. The craniofacial features included microcephaly, low-set ears, strabismus, ptosis, ocular motor apraxia, a U-shaped upper lip vermilion, short neck, and microretrognathia. The most common musculoskeletal symptoms were multiple arthrogryposis: metacarpophalangeal joint contracture, clubfoot, distal muscle weakness, Achilles tendon contracture, knee flexion contracture, camptodactyly, elbow flexion contracture, and hip subluxation.ConclusionThe ZARD phenotypes were prominent in male patients, and female patients with loss of function showed more severe symptoms. Further research is needed to clarify phenotypic variability in this rare disorder.

Effects of Chronic Inhalation of Electronic Cigarette Vapor Containing Nicotine on Neurobehaviors and Pre/Postsynaptic Neuron Markers.

Nicotine-exposed animal models exhibit neurobehavioral changes linked to impaired synaptic plasticity. Previous studies highlighted alterations in neurotransmitter levels following nicotine exposure. Vesicular glutamate transporter (VGLUT1) and vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) are essential for the transport and release of glutamate and GABA, respectively, from presynaptic neurons into synapses. In our work, an e-cigarette device was used to deliver vapor containing nicotine to C57BL/6J mice for four weeks. Novel object recognition, locomotion, and Y-maze tests were performed to investigate the behavioral parameters. Protein studies were conducted to study the hippocampal expression of VGLUT1, VGAT, and postsynaptic density protein 95 (PSD95) as well as brain cytokine markers. Long-term memory and locomotion tests revealed that e-cigarette aerosols containing nicotine modulated recognition memory and motor behaviors. We found that vapor exposure increased VGLUT1 expression and decreased VGAT expression in the hippocampus. No alterations were found in PSD95 expression. We observed that vapor-containing nicotine exposure altered certain brain cytokines such as IFNβ-1 and MCP-5. Our work provides evidence of an association between neurobehavioral changes and altered hippocampal VGLUT1 and VGAT expression in mice exposed to e-cigarette vapors containing nicotine. Such exposure was also associated with altered neurobehaviors, which might affect neurodegenerative diseases.

TDP-43 drives synaptic and cognitive deterioration following traumatic brain injury.

Traumatic brain injury (TBI) has been recognized as an important risk factor for Alzheimer's disease (AD). However, the molecular mechanisms by which TBI contributes to developing AD remain unclear. Here, we provide evidence that aberrant production of TDP-43 is a key factor in promoting AD neuropathology and synaptic and cognitive deterioration in mouse models of mild closed head injury (CHI). We observed that a single mild CHI is sufficient to exacerbate AD neuropathology and accelerate synaptic and cognitive deterioration in APP transgenic mice but repeated mild CHI are required to induce neuropathological changes and impairments in synaptic plasticity, spatial learning, and memory retention in wild-type animals. Importantly, these changes in animals exposed to a single or repeated mild CHI are alleviated by silencing of TDP-43 but reverted by rescue of the TDP-43 knockdown. Moreover, overexpression of TDP-43 in the hippocampus aggravates AD neuropathology and provokes cognitive impairment in APP transgenic mice, mimicking single mild CHI-induced changes. We further discovered that neuroinflammation triggered by TBI promotes NF-κB-mediated transcription and expression of TDP-43, which in turn stimulates tau phosphorylation and Aβ formation. Our findings suggest that excessive production of TDP-43 plays an important role in exacerbating AD neuropathology and in driving synaptic and cognitive declines following TBI.

P75NTR Ectodomain Ameliorates Cognitive Deficits and Pathologies in a Rapid Eye Movement Sleep Deprivation Mice Model

The neurotrophin receptor p75 (p75NTR) is a circadian rhythm regulator and mediates cognitive deficits induced by sleep deprivation (SD). The soluble extracellular domain of p75NTR (p75ECD) has been shown to exert a neuroprotective function in Alzheimer’s disease (AD) and depression animal models. Nevertheless, the role of p75ECD in SD-induced cognitive dysfunction is unclear. In the present study we administrated p75ECD-Fc (10, 3 mg/kg), a recombinant fusion protein of human p75ECD and fragment C of immunoglobulin IgG1, to treat mice via intraperitoneal injection. The results revealed that peripheral supplementation of high-dose p75ECD-Fc (10 mg/kg) recovered the balance between Aβ and p75ECD in the hippocampus and rescued the cognitive deficits in SD mice. We also found that p75ECD-Fc ameliorated other pathologies induced by SD, including neuronal apoptosis, synaptic plasticity impairment and neuroinflammation. The current study suggests that p75ECD-Fc is a potential candidate for SD and peripheral supplementation of p75ECD-Fc may be a prospective preventive measure for cognitive decline in SD.

The modulatory effect of 100 Hz electroacupuncture on striatal synaptic plasticity in unilateral lesioned 6-OHDA rats

Recent studied have reported that impaired striatal synaptic plasticity played a crucial role in Parkinson’s disease (PD). Previous studies have suggested that electroacupuncture (EA) alleviated the motor deficits in PD patients and animal models. However, the mechanisms underlying this protection need to be further elucidated. In this study, we found that EA-induced improvement of motor deficits in the 6-hydroxydopamine (6-OHDA) rat model doesn’t act through dopaminergic system. EA rescued the decreased striatal long-term potentiation (LTP) in 6-OHDA rats. In addition, the declined expression of N-methyl-D-aspartic acid receptor subunit 2B (NR2B) in the striatum was remarkably up-regulated by EA. The EA-induced improvement of LTP can be eliminated by NR2B-selective inhibitor. It is indicated that EA-induced recovery of striatal LTP was correlated with the up-regulation of NR2B subunit. EA was also found to rescue the decreased dendritic arborization and the spine density in the striatum of 6-OHDA rats. Meanwhile, EA suppressed striatal glutamate content and vesicular glutamate transporter 1 which is expressed in cortico-striatal glutamatergic projections. The decrease of striatal glutamate content induced by decortication, EA treatment or a combination of both reversed the loss of striatal spine density in 6-OHDA rats. It is indicated that EA-induced reduction of cortico-striatal glutamate transmission contributes to the recovery of striatal spine density. In conclusion, the therapeutic effect of EA on the motor deficits of 6-OHDA rats was mediated by rescuing cortico-striatal glutamate transmission and striatal synaptic plasticity.

Progress in the mechanism of neuronal surface P antigen modulating hippocampal function and implications for autoimmune brain disease.

The aim of this study was to present a new regulation system in the hippocampus constituted by the neuronal surface P antigen (NSPA) and the tyrosine phosphatase PTPMEG/PTPN4, which provides mechanistic and therapeutic possibilities for cognitive dysfunction driven by antiribosomal P protein autoantibodies in patients with systemic lupus erythematosus (SLE). Mice models lacking the function of NSPA as an E3 ubiquitin ligase show impaired glutamatergic synaptic plasticity, decreased levels of NMDAR at the postsynaptic density in hippocampus and memory deficits. The levels of PTPMEG/PTPN4 are increased due to lower ubiquitination and proteasomal degradation, resulting in dephosphorylation of tyrosines that control endocytosis in GluN2 NMDAR subunits. Adult hippocampal neurogenesis (AHN) that normally contributes to memory processes is also defective in the absence of NSPA. NSPA function is crucial in memory processes controlling the stability of NMDAR at PSD through the ubiquitination of PTPMEG/PTPN4 and also through AHN. As anti-P autoantibodies reproduce the impairments of glutamatergic transmission, plasticity and memory performance seen in the absence of NSPA, it might be expected to perturb the NSPA/PTPMEG/PTPN4 pathway leading to hypofunction of NMDAR. This neuropathogenic mechanism contrasts with that of anti-NMDAR antibodies also involved in lupus cognitive dysfunction. Testing this hypothesis might open new therapeutic possibilities for cognitive dysfunction in SLE patients bearing anti-P autoantibodies.

MGluR5 ablation leads to age-related synaptic plasticity impairments and does not improve Huntington’s disease phenotype

Glutamate receptors, including mGluR5, are involved in learning and memory impairments triggered by aging and neurological diseases. However, each condition involves distinct molecular mechanisms. It is still unclear whether the mGluR5 cell signaling pathways involved in normal brain aging differ from those altered due to neurodegenerative disorders. Here, we employed wild type (WT), mGluR5−/−, BACHD, which is a mouse model of Huntington’s Disease (HD), and mGluR5−/−/BACHD mice, at the ages of 2, 6 and 12 months, to distinguish the mGluR5-dependent cell signaling pathways involved in aging and neurodegenerative diseases. We demonstrated that the memory impairment exhibited by mGluR5−/− mice is accompanied by massive neuronal loss and decreased dendritic spine density in the hippocampus, similarly to BACHD and BACHD/mGluR5−/− mice. Moreover, mGluR5 ablation worsens some of the HD-related alterations. We also show that mGluR5−/− and BACHD/mGluR5−/− mice have decreased levels of PSD95, BDNF, and Arc/Arg3.1, whereas BACHD mice are mostly spared. PSD95 expression was affected exclusively by mGluR5 ablation in the aging context, making it a potential target to treat age-related alterations. Taken together, we reaffirm the relevance of mGluR5 for memory and distinguish the mGluR5 cell signaling pathways involved in normal brain aging from those implicated in HD.

Testosterone Influence on Microtubule-Associated Proteins and Spine Density in Hippocampus: Implications on Learning and Memory

The thorny protrusions or spines increase the neuronal surface area, facilitate synaptic interconnections among neurons, and play an essential role in the hippocampus. Increasing evidence suggests that testosterone, the gonadal hormone, plays an important role in neurogenesis and synaptic plasticity. The role of testosterone on microtubule-associated proteins on dendritic neurite stability in the hippocampus and its impact on learning disability is not elucidated. Adult male Wistar albino rats were randomly selected for the control, castrated, castrated + testosterone, and control + testosterone groups. Bilateral orchidectomy was done, and the testosterone propionate was administered during the entire trial period, i.e., 14 days. The learning assessments were done using working/reference memory versions of the 8-arm radial maze and hippocampal tissues processed for histological and protein expressions. There were reduced expressions of microtubule-associated protein 2 (MAP2), postsynaptic density protein 95 (PSD95), and androgen receptor (AR) and increased expression of pTau in the castrated group. Conversely, the expression of MAP2, PSD95, and AR was increased, and the pTau expression was reduced in the hippocampus of the castrated rat administrated with testosterone. Androgen-depleted rats showed impaired synaptic plasticity in the hippocampus associated with contracted microtubule dynamics. Along with learning disability, there was an increased number of reference memory errors and working memory errors in castrated rats. Observations suggest that androgen regulates expression of neural tissue-specific MAPs and plays a vital role in hippocampus synaptic plasticity and that a similar mechanism may underlie neurological disorders in aging and hypogonadal men.

JADE2 Is Essential for Hippocampal Synaptic Plasticity and Cognitive Functions in Mice

BackgroundImpairment of synaptic plasticity is closely correlated with a range of pathological conditions, such as cognitive deficits. However, how synaptic efficacy is regulated remains incompletely understood. Here, we report that the epigenetic factor JADE2 was indispensable for the maintenance of hippocampal synaptic plasticity and cognitive functions in mice. MethodsWe used the Morris water maze and the fear conditioning test to examine learning-related behaviors. In addition, Western blotting, viral-mediated JADE2 manipulations, RNA sequencing, and electrophysiological recordings were used to address our questions. ResultsJADE2 expression is increased upon enhanced neuronal activity in vitro and in vivo. Knockdown or genetic deletion of Jade2 in hippocampal CA1 results in impaired structural and functional synaptic plasticity, leading to memory impairment, whereas overexpression of JADE2 in CA1 neurons facilitates hippocampal-dependent learning and memory. Mechanistically, our data show that JADE2 modulates synaptic functions mainly by transcriptional activation of cytoskeletal regulator Rac1, and this activity is dependent on its interaction with histone acetyltransferase HBO1. Finally, we demonstrate that restoring RAC1 expression in Jade2 knockout mice could rescue the deficits in synaptic plasticity and learning-related behaviors. ConclusionsOur findings reveal that JADE2 plays a critical role in regulating synaptic plasticity and memory formation, suggesting that activity-dependent epigenetic regulation is an important molecular mechanism in controlling synaptic plasticity.

STAT4 Play A Critical Role in Aging and High Fat Diet‐Associated Decline in Long‐Term, Activity‐Dependent Potentiation of Synaptic Transmission

Aging and Alzheimer’s disease (AD) both exhibit declines in the magnitude of long‐term, activity‐dependent synaptic potentiation in humans and animals that correlate with declines in cognitive function and long‐term memory in a range of behavioral tasks. Signal Transducer and Activator of Transcription 4 (STAT4) is a transcription factor that is essential for mediating T helper 1 cell differentiation and induction of inflammatory responses to IL‐12. STAT4 plays a vital role in signaling in a range of inflammatory diseases, including cardiovascular inflammation in diabetes, systemic lupus erythematosus and rheumatoid arthritis. It is, however, unknown what role STAT4 plays in central nervous system diseases such as AD, which also have significant inflammatory components to the progression of neurodegeneration. The present study examined the effects of elimination of STAT4 signaling in transgenic mice lacking myeloid cell‐specific STAT4 expression on the expression of long‐term potentiation (LTP) of synaptic transmission, and learning and memory, in mice fed normal versus high‐fat diets. Electrophysiological recordings from Schaffer collateral‐CA1 synapses in hippocampal slices from 3 or 24 week old LysMcreStat4fl/flLdlr‐/‐ mice showed no differences in baseline synaptic transmission, paired‐pulse facilitation (PPF, a measure of presynaptic function), or LTP compared to age‐matched Stat4fl/flLdlr‐/‐ control littermates. Feeding mice a high cholesterol, high carbohydrate diet (DDC) diet from 8‐24 weeks of age resulted in marked, significant impairments in LTP compared to age‐matched mice fed a chow diet, without differences in basal transmission or PPF. In contrast to Stat4fl/flLdlr‐/‐ control mice, LysMcreStat4fl/flLdlr‐/‐ mice receiving the same DDC diet were completely protected from DDC‐associated reductions in LTP. Our current behavioral data support the idea that DDC fed Ldlr‐/‐ mice may experience cognitive and memory declines associated with early AD in comparison with LysMcreStat4fl/flLdlr‐/‐ mice. Taken together, our data support an essential role for the transcription factor STAT4 in the sensitivity of the central nervous system to DDC ‐induced impairments in synaptic plasticity and potentially cognitive function, and suggest that STAT4 pathways are a promising new target for interventions to treat neurodegenerative diseases such as Alzheimer’s, where chronic neuroinflammation is a critical disease mediator.

Synaptic plasticity and cognitive impairment consequences to acute kidney injury: Protective role of ellagic acid.

Objective(s):The goal of the current experiment was to define the efficacy and underlying molecular mechanisms of Ellagic acid (EA) on acute kidney injury (AKI) induced impairment in cognitive and synaptic plasticity in rats. Materials and Methods: Administration of 8 ml/kg glycerol (intramuscular) was used to establish the AKI model. Injured animals were treated by EA (25, 50, and 100 mg/kg, daily, gavage) for 14 consecutive days. To approve the renal injuries and the effects of EA on AKI, creatinine values in serum and urea nitrogen (BUN) values in blood were measured. Cognitive performance was investigated using the Morris water maze test. In vivo long-term potentiation (LTP) was recorded from the hippocampus. Then, the level of IL-10β and TNF-α levels were measured using ELISA kits. The integrity index of the Blood-brain barrier (BBB) was assessed by extravasation of Evans blue dye into the brain.Results:Glycerol injection increased blood urea nitrogen (BUN) and serum creatinine (Scr) levels significantly in the AKI group, and EA treatment resulted in a significant reduction in BUN levels in all concentration groups. Also, a significant reduction in the cerebral EBD concentrations was demonstrated in EA treatment rats. Moreover, the indexes of brain electrophysiology, spatial learning, and memory were improved in the EA administrated group compared with the AKI rats. Conclusion:The current experiment demonstrated the efficacy of EA in hippocampal complication and cognitive dysfunction secondary to AKI via alleviating the inflammation.