Impaired Long-term Potentiation Research Articles

Development of a platform to investigate long-term potentiation in human iPSC-derived neuronal networks.

SummaryImpairment of long-term potentiation (LTP) is a common feature of many pre-clinical models of neurological disorders; however, studies in humans are limited by the inaccessibility of the brain. Human induced pluripotent stem cells (hiPSCs) provide a unique opportunity to study LTP in disease-specific genetic backgrounds. Here we describe a multi-electrode array (MEA)-based assay to investigate chemically induced LTP (cLTP) across entire networks of hiPSC-derived midbrain dopaminergic (DA) and cortical neuronal populations that lasts for days, allowing studies of the late phases of LTP and enabling detection of associated molecular changes. We show that cLTP on midbrain DA neuronal networks is largely independent of the N-methyl-D-aspartate receptor (NMDAR) and partially dependent on brain-derived neurotrophic factor (BDNF). Finally, we describe activity-regulated gene expression induced by cLTP. This cLTP-MEA assay platform will enable phenotype discovery and higher-throughput analyses of synaptic plasticity on hiPSC-derived neurons.

Tau protein is differentially phosphorylated in young- and old-aged rats with experimentally induced hyperthyroidism.

Aging involves progressive physiological changes, including thyroid dysfunction; thus, changes in plasma thyroid hormone (TH) level may affect neuronal function such as synaptic plasticity and Tau phosphorylation. However, how Tau protein is modulated in hyperthyroidism with aging is not clear. To clarify this issue, long-term potentiation (LTP) and accompanying phosphorylation of Tau protein in different residues were investigated in the hippocampus of young and old rats with experimentally induced hyperthyroidism. The study was performed in vivo under urethane anesthesia on 2- and 12-month-old Wistar albino male rats. Field potentials, composed of a field of excitatory postsynaptic potential (fEPSP) and a population spike (PS), occurring in the hippocampal dentate gyrus region, were recorded by applying high-frequency stimulation (HFS) to the perforant pathway (100 Hz, four times at 5-min intervals) to induce LTP. Total-Tau and phosphorylated-Tau were measured in HFS-induced hippocampus by using western blotting. The TH suppressed hippocampal somatic LTP (PS) was suppressed with aging, and treatment improved this suppression in aged rats without any changes in synaptic LTP (fEPSP). The phosphorylation of Tau at Ser202/Thr205 and Thr231 residues was increased in aged control rats. Treatment of aged rats with l-thyroxine reduced the phosphorylation of Tau at these residues to the young control condition. Impaired LTP that occurs with aging may be among the underlying causes of dementia in relatively older ages, and l-thyroxine treatment restores this impaired LTP. In addition, the phosphorylation level of Tau epitopes known to play a role in the pathogenesis of Alzheimer's disease may support a critical role in the modulation of synaptic plasticity in hyperthyroidism.

The Role of Acetylcholine on the Effects of Different Doses of Sulfite in Learning and Memory.

In this study, the effects of different doses of sulfite on learning, memory, and long term potentiation as well as the relationship of these effects with acetylcholine pathways, Arc and synapsin 1 levels were investigated. Sixty male Wistar albino rats were randomly divided into three groups as control, S100, and S260. Sodiummetabisulfite (S100;100mg/kg/day, S260;260mg/kg/day) was given by oral administration. Behavioral changes were evaluated. After long term potentiation recordings from the perforant pathway-dentate gyrus synapses, animals were sacrificed. Acetylcholinesterase activity, choline acetyltransferase activity, acetylcholine level as well as Arc and Synapsin 1 expressions were analyzed on the hippocampi. The total distance and average velocity values in the open field and Morris water maze tests increased in the sulfite groups, while the discrimination index in the novel object recognition test decreased compared to controls. Acetylcholine levels and choline acetyltransferase activity were also increased in the sulfite groups, while acetylcholinesterase activity was decreased compared to controls. Sulfite intake attenuated long term potentiation in the hippocampus. It has been observed that the excitatory postsynaptic potential slope and population spike amplitude of the field potentials obtained in sulfite groups decreased. This impairment was accompanied by a decrease in Arc and synapsin 1 expressions. In conclusion, it has been shown that sulfite intake in adults impairs learning and memory, possibly mediated by the cholinergic pathway. It is considered that the decrement in Arc and synapsin expressions may play a role in the mechanism underlying the impairment in long term potentiation caused by toxicity.

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.

Nicotine alleviates alcohol-induced memory and long-term potentiation impairment

Alcohol and nicotine are routinely abused together. There is one plausible explanation that comorbidity can alleviate alcohol-induced cognitive impairment. However, the mechanism involved is not known. The aim of this report was to evaluate the interactive effects of alcohol coadministration with nicotine on hippocampal memory and long-term potentiation (LTP). C57BL/6 mice were distributed into 4 treatment groups: control, alcohol, nicotine, and alcohol plus nicotine. All mice received tap water or alcohol solution and saline or nicotine. In water maze test, the alcohol group showed significant decreases in hippocampus function and acquisition training than control, nicotine, and combined treatment groups. The alcohol group also showed a significantly shorter latency in entering the foot-shock compartment than control, nicotine, and combined treatment groups in a passive avoidance test. Theta burst stimulation was adopted to induce concrete LTP in CA1 field recording using hippocampal slice. Alcohol alone administration failed to maintain LTP. Nicotine alone administration did not alter hippocampal LTP. There were no negative effects of alcohol on hippocampal LTP in mice administrated with nicotine. The current study successfully demonstrated beneficial effects of nicotine on alcohol induced memory impairment accompanied by hippocampal LTP impairment after one week of co-administration and one-day withdrawal.

Aβ oligomers from human brain impair mossy fiber LTP in CA3 of hippocampus, but activating cAMP-PKA and cGMP-PKG prevents this

Early cognitive impairment in Alzheimer's disease may result in part from synaptic dysfunction caused by the accumulation oligomeric assemblies of amyloid β-protein (Aβ). Changes in hippocampal function seem critical for cognitive impairment in early Alzheimer's disease (AD). Diffusible oligomers of Aβ (oAβ) have been shown to block canonical long-term potentiation (LTP) in the CA1 area of hippocampus, but whether there is also a direct effect of oAβ on synaptic transmission and plasticity at synapses between mossy fibers (axons) from the dentate gyrus granule cells and CA3 pyramidal neurons (mf-CA3 synapses) is unknown. Studies in APP transgenic mice have suggested an age-dependent impairment of mossy fiber LTP. Here we report that although endogenous AD brain-derived soluble oAβ had no effect on mossy-fiber basal transmission, it strongly impaired paired-pulse facilitation in the mossy fiber pathway and presynaptic mossy fiber LTP (mf-LTP). Selective activation of both β1 and β2 adrenergic receptors and their downstream cAMP/PKA signaling pathway prevented oAβ-mediated inhibition of mf-LTP. Unexpectedly, activation of the cGMP/PKG signaling pathway also prevented oAβ-impaired mf-LTP. Our results reveal certain specific pharmacological targets to ameliorate human oAβ-mediated impairment at the mf-CA3 synapse.

Trans-Anethole Alleviates Trimethyltin Chloride-Induced Impairments in Long-Term Potentiation.

Trans-anethole is an aromatic compound that has been studied for its anti-inflammation, anticonvulsant, antinociceptive, and anticancer effects. A recent report found that trans-anethole exerted neuroprotective effects on the brain via multiple pathways. Since noxious stimuli may both induce neuronal cell injury and affect synaptic functions (e.g., synaptic transmission or plasticity), it is important to understand whether the neuroprotective effect of trans-anethole extends to synaptic plasticity. Here, the effects of trimethyltin (TMT), which is a neurotoxic organotin compound, was investigated using the field recording method on hippocampal slice of mice. The influence of trans-anethole on long-term potentiation (LTP) was also studied for both NMDA receptor-dependent and NMDA receptor–independent cases. The action of trans-anethole on TMT-induced LTP impairment was examined, too. These results revealed that trans-anethole enhances NMDA receptor-dependent and -independent LTP and alleviates TMT-induced LTP impairment. These results suggest that trans-anethole modulates hippocampal LTP induction, prompting us to speculate that it may be helpful for improving cognitive impairment arising from neurodegenerative diseases, including Alzheimer’s disease.

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.

E4BP4 Coordinates Circadian Control of Cognition in Delirium.

Improved understanding of the etiologies of delirium, a common and severe neuropsychiatric syndrome, would facilitate the disease prevention and treatment. Here, the authors invesitgate the role of circadian rhythms in the pathogenesis of delirium. They observe perturbance of circadian rhythms in mouse models of delirium and disrupted clock gene expression in patients with delirium. In turn, physiological and genetic circadian disruptions sensitize mice to delirium with aggravated cognitive impairment. Likewise, global deletion of E4bp4 (E4 promoter‐binding protein), a clock gene markedly altered in delirium conditions, results in exacerbated delirium‐associated cognitive decline. Cognitive decline in delirium models is attributed to microglial activation and impaired long‐term potentiation in the hippocampus. Single‐cell RNA‐sequencing reveals microglia as the regulatory target of E4bp4. E4bp4 restrains microglial activation via inhibiting the ERK1/2 signaling pathway. Supporting this, mice lacking in microglial E4bp4 are delirious prone, whereas mice with E4bp4 specifically deleted in hippocampal CA1 neurons have a normal phenotype. Mechanistically, E4bp4 inhibits ERK1/2 signaling by trans‐repressing Mapk1/3 (genes encoding ERK1/2) via direct binding to a D‐box element in the promoter region. These findings define a causal role of clock dysfunction in delirium development and indicate E4bp4 as a regulator of cognition at the crosstalk between circadian clock and delirium.

MTORC1 function in hippocampal parvalbumin interneurons: regulation of firing and long-term potentiation of intrinsic excitability but not long-term contextual fear memory and context discrimination

Hippocampal CA1 parvalbumin-expressing interneurons (PV INs) play a central role in controlling principal cell activity and orchestrating network oscillations. PV INs receive excitatory inputs from CA3 Schaffer collaterals and local CA1 pyramidal cells, and they provide perisomatic inhibition. Schaffer collateral excitatory synapses onto PV INs express Hebbian and anti-Hebbian types of long-term potentiation (LTP), as well as elicit LTP of intrinsic excitability (LTPIE). LTPIE requires the activation of type 5 metabotropic glutamate receptors (mGluR5) and is mediated by downregulation of potassium channels Kv1.1. It is sensitive to rapamycin and thus may involve activation of the mammalian target of rapamycin complex 1 (mTORC1). LTPIE facilitates PV INs recruitment in CA1 and maintains an excitatory-inhibitory balance. Impaired CA1 PV INs activity or LTP affects network oscillations and memory. However, whether LTPIE in PV INs plays a role in hippocampus-dependent memory remains unknown. Here, we used conditional deletion of the obligatory component of mTORC1, the Regulatory-Associated Protein of mTOR (Raptor), to directly manipulate mTORC1 in PV INs. We found that homozygous, but not heterozygous, conditional knock-out of Rptor resulted in a decrease in CA1 PV INs of mTORC1 signaling via its downstream effector S6 phosphorylation assessed by immunofluorescence. In whole-cell recordings from hippocampal slices, repetitive firing of CA1 PV INs was impaired in mice with either homozygous or heterozygous conditional knock-out of Rptor. High frequency stimulation of Schaffer collateral inputs that induce LTPIE in PV INs of control mice failed to do so in mice with either heterozygous or homozygous conditional knock-out of Rptor in PV INs. At the behavioral level, mice with homozygous or heterozygous conditional knock-out of Rptor showed similar long-term contextual fear memory or contextual fear memory discrimination relative to control mice. Thus, mTORC1 activity in CA1 PV INs regulates repetitive firing and LTPIE but not consolidation of long-term contextual fear memory and context discrimination. Our results indicate that mTORC1 plays cell-specific roles in synaptic plasticity of hippocampal inhibitory interneurons that are differentially involved in hippocampus-dependent learning and memory.

Histamine H3 receptor antagonist, ciproxifan, alleviates cognition and synaptic plasticity alterations in a valproic acid-induced animal model of autism

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and cognitive behaviors. Histamine H3 receptor (H3R) antagonists are considered as therapeutic factors for treating cognitive impairments. The aim of the present study was to evaluate the effects of the H3R antagonist, ciproxifan (CPX), on cognition impairment especially, spatial learning memory, and synaptic plasticity in the CA1 region of the hippocampus in autistic rats. Pregnant rats were injected with either valproic acid (VPA) (600 mg/kg, i.p.) or saline on an embryonic day 12.5 (E12.5). The effects of the H3R antagonist, ciproxifan (CPX) (1, 3 mg/kg, i.p.), were investigated on learning and memory in VPA-exposed rat pups and saline-exposed rat pups using Morris water maze (MWM) and social interaction tasks. The H2R antagonist, famotidine (FAM) (10, 20, 40 mg/kg, i.p.), was used to determine whether brain histaminergic neurotransmission exerted its procognitive effects through the H2R. In addition, synaptic reinforcement was evaluated by in vivo field potential recording. The results showed that VPA-exposed rat pups had significantly lower sociability and social memory performance compared to the saline rats. VPA-exposed rat pups exhibited learning and memory impairments in the MWM task. In addition, VPA caused suppression of long-term potentiation (LTP) in the CA1 area of the hippocampus. Our results demonstrated that CPX 3 mg/kg improved VPA-induced cognitive impairments and FAM 20 mg/kg attenuated cognitive behaviors as well as electrophysiological properties. CPX 3 mg/kg improved VPA-induced impairments of LTP as well as learning and memory deficits through H2R.

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.

Developmental Hypothyroidism Influences the Development of the Entorhinal-Dentate Gyrus Pathway of Rat Offspring.

BackgroundDevelopmental hypothyroidism impairs learning and memory in offspring, which depend on extensive neuronal circuits in the entorhinal cortex, together with the hippocampus and neocortex. The entorhinal-dentate gyrus pathway is the main entrance of memory circuits. We investigated whether developmental hypothyroidism impaired the morphological development of the entorhinal-dentate gyrus pathway.MethodsWe examined the structure and function of the entorhinal-dentate gyrus pathway in response to developmental hypothyroidism induced using 2-mercapto-1-methylimidazole.Results1,1´-Dioctadecyl-3,3,3´,3´-tetramethylindocarbocyanine perchlorate tract tracing indicated that entorhinal axons showed delayed growth in reaching the outer molecular layer of the dentate gyrus at postnatal days 2 and 4 in hypothyroid conditions. The proportion of fibers in the outer molecular layer was significantly smaller in the hypothyroid group than in the euthyroid group at postnatal day 4. At postnatal day 10, the pathway showed a layer-specific distribution in the outer molecular layer, similar to the euthyroid group. However, the projected area of entorhinal axons was smaller in the hypothyroid group than in the euthyroid group. An electrophysiological examination showed that hypothyroidism impaired the long-term potentiation of the perforant and the cornu ammonis 3–cornu ammonis 1 pathways. Many repulsive axon guidance molecules were involved in the formation of the entorhinaldentate gyrus pathway. The hypothyroid group had higher levels of erythropoietin-producing hepatocyte ligand A3 and semaphorin 3A than the euthyroid group.ConclusionWe demonstrated that developmental hypothyroidism might influence the development of the entorhinal-dentate gyrus pathway, contributing to impaired long-term potentiation. These findings improve our understanding of neural mechanisms for memory function.

Chronic exposure of alcohol triggers microglia-mediated synaptic elimination inducing cognitive impairment

Background and aimsLong-term alcohol intake leads to cognitive impairment and dementia. The impairment of the cerebral cortex and limbic structures in alcoholics is associated with the loss of synapses instead of neurons. Synapse loss is considered to be an early and key feature of many neurodegenerative diseases, in which microglia-mediated synapse elimination is vital. However, the underlying mechanisms of synapse loss and cognitive impairment caused by long-term alcohol intake are still largely unknown. MethodsWe investigated the relationship of synapse impairment, the microglial innate immune receptor—TREM2, and microglia-mediated synaptic elimination in long-term alcohol exposure. ResultsWe found that long-term alcohol exposure increased expression of TREM2, decreased expression of synaptic proteins and glutamate receptor subunits, reduced dendrite spine density, and impaired long-term potentiation (LTP) in the hippocampus. Minocycline reduced the amount of the postsynaptic marker PSD95 in microglia, attenuated dendrite spine density loss, and slow down the forgetting process of already-formed memory. Furthermore, we found that TREM2 participated in microglia-mediated synapse elimination in chronic alcohol exposure in vivo. Significantly fewer PSD95 were detectable in microglial phagolysosomes in TREM2 knockdown mice. Besides, TREM2 gene silencing ameliorated synapse loss, LTP impairment, and forgetting of remote memories. ConclusionsOur data suggests that TREM2 is associated with synaptic plasticity impairment and memory deficits, indicating microglia-mediated synaptic pruning might be the underlying mechanism involved in synapse loss and memory impairment induced by long-term alcohol intake. These findings provide new evidence for the receptor's participation in neurodegeneration diseases.

Differences in hippocampal plasticity and memory outcomes in anterior versus posterior cerebellar stroke

Neurological symptoms following cerebellar stroke can range from motor to cognitive-affective impairments. Topographic imaging studies from patients with lesions confined to the cerebellum have shown evidence linking anterior cerebellar lobules with motor function and posterior lobules with cognitive function. Damage to the cerebellum can disrupt functional connectivity in cerebellar stroke patients, as it is highly interconnected with forebrain motor and cognitive areas. The hippocampus plays a key role in memory acquisition, a cognitive domain that is negatively impacted by posterior cerebellar stroke, and there is increasing evidence that the cerebellum can affect hippocampal function in health and disease. To study these topographical dissociations, we developed a mouse photo-thrombosis model to produce unilateral strokes in anterior (lobules III-V) or posterior (lobules VI-VIII) cerebellar cortex to examine hippocampal plasticity and behavior. Histological and MRI data demonstrate reproducible injury that is confined to the targeted lobules. We then measured hippocampal long-term potentiation (LTP) ex-vivo with extracellular field recording experiments in acute brain slices obtained from mice 7 days post-cerebellar stroke. Interestingly, we found that a unilateral posterior stroke resulted in a contralateral hippocampal impairment, matching the cerebellothalamic pathway trajectory, while LTP was intact in both hippocampi of mice with anterior strokes. We also assessed motor coordination and memory function at 7 days post-stroke using a balance beam, contextual and delay fear conditioning (CFC and DFC), and novel object recognition (NOR) tasks. Mice with anterior strokes showed lack of coordination evaluated as an increased number of missteps, while mice with posterior strokes did not. Mice with anterior or posterior cerebellar strokes demonstrated similar freezing behavior to shams in CFC and DFC, while only posterior stroke mice displayed a reduced discrimination index in the NOR task. These data suggest that a unilateral LTP impairment observed in mice with posterior strokes produces a mild memory impairment. Our results demonstrate that our model recapitulates aspects of clinical lesion-symptom mapping, with anterior cerebellar strokes producing impaired motor coordination and posterior cerebellar strokes producing an object-recognition memory impairment. Further studies are warranted to interrogate other motor and cognitive-affective behaviors and brain region specific alterations following focal cerebellar stroke. The novel model presented herein will allow for future preclinical translational studies to improve neurological deficits after cerebellar stroke.

Stachyose Alleviates Corticosterone-Induced Long-Term Potentiation Impairment via the Gut-Brain Axis.

Stress can induce learning and memory impairment; corticosterone is often used to study the effects and mechanisms of stress in animal models. Long-term potentiation (LTP) has been widely used for tackling the mechanisms of memory. Liuwei Dihuang decoction-active fraction combination (LW-AFC) can improve stress-induced LTP and cognition impairment; stachyose is an oligosaccharide in LW-AFC. The effects and mechanisms of stachyose on stress are unknown. In this study, stachyose showed protective effects against LTP impairment by corticosterone in vivo only via intragastric administration for 7 consecutive days, but there was little effect even after direct intracerebroventricular injection; the protective effect of stachyose could be canceled by non-absorbable antibiotics (ATB) which disturbed gut flora. 16S rRNA sequencing, alpha diversity, and principal coordinate analysis (PCoA) revealed that the gut flora in corticosterone-treated mice was disturbed and stachyose could improve corticosterone-induced gut flora disturbance. Bacteroidetes were decreased and Deferribacteres were increased significantly in corticosterone-treated mice, and stachyose restored Bacteroidetes and Deferribacteres to the normal level. D-serine, a coactivator of NMDA receptors, plays an important role in synaptic plasticity and cognition. Here, corticosterone had little effect on the content of D-serine and L-serine (the precursor of D-serine), but it reduced the D-serine release-related proteins, Na+-independent alanine–serine–cysteine transporter-1 (ASC-1), and vesicle-associated membrane protein 2 (VAMP2) significantly in hippocampus; stachyose significantly increased ASC-1 and VAMP2 in corticosterone-treated mice, and ATB blocked stachyose’s effects on ASC-1 and VAMP2. NMDA receptors co-agonists L-serine, D-serine, and glycine significantly improved LTP impairment by corticosterone. These results indicated that stachyose might indirectly increase D-serine release through the gut–brain axis to improve LTP impairment by corticosterone in the hippocampus in vivo.

Advanced maternal age impairs synaptic plasticity in offspring rats

Advanced maternal age (AMA) has become more common in the last decade and is associated with poor neurodevelopmental outcomes in offspring. Neurocognitive and emotional development is associated with synaptic structural and functional plasticity. In the present study, we investigated the relationship between AMA and synapse plasticity in the offspring. We examined the synaptic ultrastructure, synapse-related proteins and long-term potentiation (LTP) in the offspring of Sprague–Dawley female rats aged 12 months (AMA group) and 3 months (Control group) on postnatal (P) days 7, 14, 28 and 60. Immunofluorescence analysis revealed decreases in the expression of neurofilament 200 (NF200) and axon length in the AMA group compared with the control group at P14. Western blot analysis showed that the expression of postsynaptic density-95 (PSD-95) and synaptophysin (SYP) was reduced in the immature offspring of the AMA group at P7. Transmission electron microscopy showed decreased thickness of the PSD and increased length of the active zone (AZ) in the offspring of the AMA group. Electrophysiological recordings in hippocampal slices revealed impaired LTP in the AMA offspring. Our data suggest that AMA impairs the synaptic plasticity of offspring, which may underlie the mechanism of neurodevelopmental disorders.

Microglial large extracellular vesicles propagate early synaptic dysfunction in Alzheimer’s disease

Synaptic dysfunction is an early mechanism in Alzheimer’s disease that involves progressively larger areas of the brain over time. However, how it starts and propagates is unknown.Here we show that amyloid-β released by microglia in association with large extracellular vesicles (Aβ-EVs) alters dendritic spine morphology in vitro, at the site of neuron interaction, and impairs synaptic plasticity both in vitro and in vivo in the entorhinal cortex–dentate gyrus circuitry. One hour after Aβ-EV injection into the mouse entorhinal cortex, long-term potentiation was impaired in the entorhinal cortex but not in the dentate gyrus, its main target region, while 24 h later it was also impaired in the dentate gyrus, revealing a spreading of long-term potentiation deficit between the two regions. Similar results were obtained upon injection of extracellular vesicles carrying Aβ naturally secreted by CHO7PA2 cells, while neither Aβ42 alone nor inflammatory extracellular vesicles devoid of Aβ were able to propagate long-term potentiation impairment. Using optical tweezers combined to time-lapse imaging to study Aβ-EV–neuron interaction, we show that Aβ-EVs move anterogradely at the axon surface and that their motion can be blocked through annexin-V coating. Importantly, when Aβ-EV motility was inhibited, no propagation of long-term potentiation deficit occurred along the entorhinal–hippocampal circuit, implicating large extracellular vesicle motion at the neuron surface in the spreading of long-term potentiation impairment.Our data indicate the involvement of large microglial extracellular vesicles in the rise and propagation of early synaptic dysfunction in Alzheimer’s disease and suggest a new mechanism controlling the diffusion of large extracellular vesicles and their pathogenic signals in the brain parenchyma, paving the way for novel therapeutic strategies to delay the disease.

Eugenitol ameliorates memory impairments in 5XFAD mice by reducing Aβ plaques and neuroinflammation

Alzheimer’s disease (AD) is caused by various pathological mechanisms; therefore, it is necessary to develop drugs that simultaneously act on multiple targets. In this study, we investigated the effects of eugenitol, which has anti-amyloid β (Aβ) and anti-neuroinflammatory effects, in an AD mouse model. We found that eugenitol potently inhibited Aβ plaque and oligomer formation. Moreover, eugenitol dissociated the preformed Aβ plaques and reduced Aβ-induced nero2a cell death. An in silico docking simulation study showed that eugenitol may interact with Aβ1–42 monomers and fibrils. Eugenitol showed radical scavenging effects and potently reduced the release of proinflammatory cytokines from lipopolysaccharide-treated BV2 cells. Systemic administration of eugenitol blocked Aβ aggregate-induced memory impairment in the Morris water maze test in a dose-dependent manner. In 5XFAD mice, prolonged administration of eugenitol ameliorated memory and hippocampal long-term potentiation impairment. Moreover, eugenitol significantly reduced Aβ deposits and neuroinflammation in the hippocampus of 5XFAD mice. These results suggest that eugenitol, which has anti-Aβ aggregation, Aβ fibril dissociation, and anti-inflammatory effects, potently modulates AD-like pathologies in 5XFAD mice, and could be a promising candidate for AD therapy.

Neurodegeneration-related genes are differentially expressed in middle-aged rats compared to young-adult rats having equal performance on long-term memory and synaptic plasticity

The present study is concerned with assessing differences in plasticity-induced neurodegeneration-related gene expressions and tau phosphorylation between young-aged and middle-aged rats. The experiments were carried out in vivo under urethane anesthesia on adult male Wistar rats between the ages of 2-3 months and 11-12 months. Field potentials, composed of a field of excitatory-postsynaptic potential (fEPSP) and a population-spike (PS), were recorded from granule cells of the dentate gyrus. Plasticity was induced by high-frequency (HFS) or low frequency stimulation (LFS). mRNA of neurodegeneration-related genes and total-and phosphorylated-tau were measured in HFS-and LFS-induced hippocampus by using quantitative rt-PCR and Western blotting. In addition, naive rats (unstimulated) were tested for spatial learning and memory with a 5-day Morris water maze (MWM). HFS-induced LTP of PS had attenuated in middle-aged rats, but there were no gross differences in baseline synaptic function, HFS-induced fEPSP and LFS-induced fEPSP, and PS plasticity between young-aged and middle-aged rats. Relative to young-aged rats, in middle-aged rats, HFS-induced MAPT, CDK5, and AKT1 genes were more up regulated, while LFS-induced Bace1, PSEN2, CAPN1, ANXA, CDK5, and GSK-3β genes were more down-regulated. Tau and p-tauThr231 were increased by HFS/LFS in the hippocampus of middle-aged rats compared to those of young-aged rats. In MWM, despite the difference in searching strategy of both age groups of rats, memory was not affected by age. Impaired long-term potentiation (LTP) and accompanying changes in intracellular biological markers may underlie in neurodegenerative disease characterized by dementia that occurs gradually later ages. However, these changes were not reflected in behavioral spatial memory.