Hippocampal CA1 Long-term Potentiation Research Articles

Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder

BackgroundMutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5−/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5−/y rats.MethodsTo allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology.ResultsOur results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5−/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5−/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses.ConclusionsOur data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity.LimitationsThis study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

MiR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1-containing AMPA receptors in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3′-untranslated region (3′ UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

A juvenile mouse model of anti-N-methyl-D-aspartate receptor encephalitis by active immunization.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis, and it is associated with psychosis, dyskinesia, and seizures. Anti-NMDAR encephalitis (NMDARE) in juveniles and adults presents different clinical charactreistics. However, the pathogenesis of juvenile anti-NMDAR encephalitis remains unclear, partly because of a lack of suitable animal models. We developed a model of juvenile anti-NMDAR encephalitis using active immunization with an amino terminal domain peptide from the GluN1 subunit (GluN1356 - 385) against NMDARs in 3-week-old female C57BL/6J mice. Immunofluorescence staining suggested that autoantibody levels in the hippocampus increased, and HEK-293T cells staining identified the target of the autoantibodies as GluN1, suggesting that GluN1-specific immunoglobulin G was successfully induced. Behavior assessment showed that the mice suffered significant cognition impairment and sociability reduction, which is similar to what is observed in patients affected by anti-NMDAR encephalitis. The mice also exhibited impaired long-term potentiation in hippocampal CA1. Pilocarpine-induced epilepsy was more severe and had a longer duration, while no spontaneous seizures were observed. The juvenile mouse model for anti-NMDAR encephalitis is of great importance to investigate the pathological mechanism and therapeutic strategies for the disease, and could accelerate the study of autoimmune encephalitis.

Adenosine A2A Receptor Up-Regulation Pre-Dates Deficits of Synaptic Plasticity and of Memory in Mice Exposed to Aβ1-42 to Model Early Alzheimer's Disease.

The intracerebroventricular (icv) injection of amyloid peptides (Aβ) models Alzheimer's disease (AD) in mice, as typified by the onset within 15 days of deficits of memory and of hippocampal long-term potentiation (LTP) that are prevented by the blockade of adenosine A2A receptors (A2AR). Since A2AR overfunction is sufficient to trigger memory deficits, we tested if A2AR were upregulated in hippocampal synapses before the onset of memory deficits to support the hypothesis that A2AR overfunction could be a trigger of AD. Six to eight days after Aβ-icv injection, mice displayed no alterations of hippocampal dependent memory; however, they presented an increased excitability of hippocampal synapses, a slight increase in LTP magnitude in Schaffer fiber-CA1 pyramid synapses and an increased density of A2AR in hippocampal synapses. A2AR blockade with SCH58261 (50 nM) normalized excitability and LTP in hippocampal slices from mice sacrificed 7-8 days after Aβ-icv injection. Fifteen days after Aβ-icv injection, mice displayed evident deficits of hippocampal-dependent memory deterioration, with reduced hippocampal CA1 LTP but no hyperexcitability and a sustained increase in synaptic A2AR, which blockade restored LTP magnitude. This shows that the upregulation of synaptic A2AR precedes the onset of deterioration of memory and of hippocampal synaptic plasticity, supporting the hypothesis that the overfunction of synaptic A2AR could be a trigger of memory deterioration in AD.

Epileptiform activity influences theta-burst induced LTP in the adult hippocampus: a role for synaptic lipid raft disruption in early metaplasticity?

Non-epileptic seizures are identified as a common epileptogenic trigger. Early metaplasticity following seizures may contribute to epileptogenesis by abnormally altering synaptic strength and homeostatic plasticity. We now studied how in vitro epileptiform activity (EA) triggers early changes in CA1 long-term potentiation (LTP) induced by theta-burst stimulation (TBS) in rat hippocampal slices and the involvement of lipid rafts in these early metaplasticity events. Two forms of EA were induced: (1) interictal-like EA evoked by Mg2+ withdrawal and K+ elevation to 6 mM in the superfusion medium or (2) ictal-like EA induced by bicuculline (10 μM). Both EA patterns induced and LTP-like effect on CA1 synaptic transmission prior to LTP induction. LTP induced 30 min post EA was impaired, an effect more pronounced after ictal-like EA. LTP recovered to control levels 60 min post interictal-like EA but was still impaired 60 min after ictal-like EA. The synaptic molecular events underlying this altered LTP were investigated 30 min post EA in synaptosomes isolated from these slices. EA enhanced AMPA GluA1 Ser831 phosphorylation but decreased Ser845 phosphorylation and the GluA1/GluA2 ratio. Flotillin-1 and caveolin-1 were markedly decreased concomitantly with a marked increase in gephyrin levels and a less prominent increase in PSD-95. Altogether, EA differentially influences hippocampal CA1 LTP thorough regulation of GluA1/GluA2 levels and AMPA GluA1 phosphorylation suggesting that altered LTP post-seizures is a relevant target for antiepileptogenic therapies. In addition, this metaplasticity is also associated with marked alterations in classic and synaptic lipid raft markers, suggesting these may also constitute promising targets in epileptogenesis prevention.

Midazolam at Low Nanomolar Concentrations Affects Long-term Potentiation and Synaptic Transmission Predominantly via the α1-γ-Aminobutyric Acid Type A Receptor Subunit in Mice.

Midazolam amplifies synaptic inhibition via different γ-aminobutyric acid type A (GABAA) receptor subtypes defined by the presence of α1-, α2-, α3-, or α5-subunits in the channel complex. Midazolam blocks long-term potentiation and produces postoperative amnesia. The aims of this study were to identify the GABAA receptor subtypes targeted by midazolam responsible for affecting CA1 long-term potentiation and synaptic inhibition in neocortical neurons. The effects of midazolam on hippocampal CA1 long-term potentiation were studied in acutely prepared brain slices of male and female mice. Positive allosteric modulation on GABAA receptor-mediated miniature inhibitory postsynaptic currents was investigated in organotypic slice cultures of the mouse neocortex. In both experiments, wild-type mice and GABAA receptor knock-in mouse lines were compared in which α1-, α5-, α1/2/3-, α1/3/5- and α2/3/5-GABAA receptor subtypes had been rendered benzodiazepine-insensitive. Midazolam (10 nM) completely blocked long-term potentiation (mean ± SD, midazolam, 98 ± 11%, n = 14/8 slices/mice vs. control 156 ± 19%, n = 20/12; P < 0.001). Experiments in slices of α1-, α5-, α1/2/3-, α1/3/5-, and α2/3/5-knock-in mice revealed a dominant role for the α1-GABAA receptor subtype in the long-term potentiation suppressing effect. In slices from wild-type mice, midazolam increased (mean ± SD) charge transfer of miniature synaptic events concentration-dependently (50 nM: 172 ± 71% [n = 10/6] vs. 500 nM: 236 ± 54% [n = 6/6]; P = 0.041). In α2/3/5-knock-in mice, charge transfer of miniature synaptic events did not further enhance when applying 500 nM midazolam (50 nM: 171 ± 62% [n = 8/6] vs. 500 nM: 175 ± 62% [n = 6/6]; P = 0.454), indicating two different binding affinities for midazolam to α2/3/5- and α1-subunits. These results demonstrate a predominant role of α1-GABAA receptors in the actions of midazolam at low nanomolar concentrations. At higher concentrations, midazolam also enhances other GABAA receptor subtypes. α1-GABAA receptors may already contribute at sedative doses to the phenomenon of postoperative amnesia that has been reported after midazolam administration.

Developmental deltamethrin: Sex-specific hippocampal effects in Sprague Dawley rats

Pyrethroid pesticides are widely used and can cause long-term effects after early exposure. Epidemiological and animal studies reveal associations between pyrethroid exposure and altered cognition following prenatal and/or neonatal exposure. However, little is known about the cellular effects of such exposure. Sprague Dawley rats were gavaged with 0 or 1.0 mg/kg deltamethrin (DLM), a Type II pyrethroid, in corn oil (dose volume 5 mL/kg) once per day from postnatal day (P) 3–20 and assessed shortly after dosing ended or as adults. No effects of DLM exposure were found on striatal dopaminergic markers, nor on AMPA receptor subunits or on NMDA-NR1. However, DLM increased NMDA-NR2A and decreased NMDA-NR2B levels in the hippocampus, in males but not females. Additionally, adult hippocampal CA1 long-term potentiation was increased in DLM-treated males but not females. Potassium stimulated extracellular glutamate release in the hippocampus was not affected using in vivo microdialysis. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) showed increased apoptotic cells in the dentate gyrus of male rats, in the absence of changes in cleaved caspase-3 at P21. Proinflammatory cytokines interferon gamma trended up in striatum, interleukin-1β trended down in nucleus accumbens, IL-13 trended up in hippocampus, and keratinocyte chemoattractant/human growth-regulated oncogene (KC/GRO or CXCL1) was significantly increased in the hippocampus in male DLM-treated rats on P20. The data point to the developing hippocampus as a susceptible region to DLM-induced adverse effects.

Histone Deacetylase 2 Knockdown Ameliorates Morphological Abnormalities of Dendritic Branches and Spines to Improve Synaptic Plasticity in an APP/PS1 Transgenic Mouse Model.

Disease-modifying therapies, such as neuroprotective and neurorestorative interventions, are strongly desired for Alzheimer’s disease (AD) treatment. Several studies have suggested that histone deacetylase 2 (HDAC2) inhibition can exhibit disease-modifying effects in AD patients. However, whether HDAC2 inhibition shows neuroprotective and neurorestorative effects under neuropathic conditions, such as amyloid β (Aβ)-elevated states, remains poorly understood. Here, we performed HDAC2-specific knockdown in CA1 pyramidal cells and showed that HDAC2 knockdown increased the length of dendrites and the number of mushroom-like spines of CA1 basal dendrites in APP/PS1 transgenic mouse model. Furthermore, HDAC2 knockdown also ameliorated the deficits in hippocampal CA1 long-term potentiation and memory impairment in contextual fear conditioning tests. Taken together, our results support the notion that specific inhibition of HDAC2 has the potential to slow the disease progression of AD through ameliorating Aβ-induced neuronal impairments.

Dihydroartemisinin Induces O-GlcNAcylation and Improves Cognitive Function in a Mouse Model of Tauopathy.

Tauopathies are a group of neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau pathology. Hyperphosphorylation modification promotes tau protein misfolding and aggregation into neurofibrillary tangles, leading to impairments of synaptic plasticity and learning and memory. However, very limited therapeutic strategies are available. In the present study, we wanted to investigate the potential effects of Dihydroartemisinin (DHA) on tauopathies. We constructed adeno-associated virus carrying hTau cDNA (AAVhTau) to establish a mouse model of tauopathy through intrahippocampal microinjection. Using a combination of behavioral test, electrophysiological recording, and western blotting assay, we examined the neuroprotective effects of DHA on learning and memory deficits in mice with tauopathy. DHA improved learning and memory and increased hippocampal CA1 long-term potentiation (LTP) in mice overexpressed human tau (hTau) in the hippocampus. More importantly, further study revealed that DHA could induce protein O-GlcNAcylation modification and reduce protein phosphorylation. O-GlcNAc transferase inhibitor alloxan could suppress DHA-induced protein O-GlcNAcylation, and subsequently prevent therapeutic effect of DHA on the deficits of learning and memory as well as synaptic plasticity in hTau mice. These results indicate that DHA may exert neuroprotective role in tauopathy through a crosstalk between O-GlcNAcylation and phosphorylation, suggesting a potential therapeutic for learning and memory deficits associated with tau pathology.

Attenuation of IL‐6 Signalling Enhances Hippocampal Long‐Term Potentiation in Dystrophin‐Deficient mdx Mice

In addition to progressive immobility, boys with Duchenne muscular dystrophy commonly exhibit cognitive impairment1, a trait also exhibited by mdx mice, which similarly lack hippocampal dystrophin. Interleukin (IL)-6 is also linked to impaired cognitive function2 and is elevated in dystrophinopathies. Hippocampal long term potentiation (LTP) is the proposed molecular correlate of memory formation, but descriptions of this phenomenon in mdx mice are conflicting3. The aim of the present study was to assess hippocampal LTP in wild type (WT) and mdx mice and to determine whether blocking IL-6 signalling modified LTP in mdx mice. In accordance with the European Directive 2010/63/EU, mdx and WT mice (8-12 weeks old) were anaesthetised with isoflurane. An intrathecal injection of monoclonal anti-IL-6 receptor antibodies (xIL-6R, 0.2mg/kg) or saline was administered and recognition memory was assessed using the novel object recognition test. After euthanasia, LTP, induced by high frequency stimulation of Schaffer collateral-CA1 fibres, was compared between mdx and WT mice, in both untreated and treated mice. All fEPSP slope speeds (mV/ms) are provided as a normalised percentage of averaged 20-minute fEPSP slope pre-LTP baselines. Statistical analyses were performed using 2-way ANOVA and unpaired t tests with data expressed as mean normalised post-LTP slope speed ± SEM. Contrary to previous studies3, the magnitude of LTP was reduced in untreated mdx slices relative to WT (2-way ANOVA, Interaction – F (179, 2327) = 1.370, p=0.0012, Genotype – F (1, 13) = 8.517, p=0.0120, n=6-9). Importantly, following in vivo administration of xIL-6R, the slope of the post-LTP excitatory post synaptic potential (EPSP) was enhanced in mdx hippocampal slices in comparison to in vivo administration of saline in mdx mice (mdx saline 199.5 ± 15.90, mdx xIL-6R 282.3 ± 3.528, n=3-4, p= 0.0074). No change was detected in WT mice. With regards to behaviour, novel object recognition in mdx mice was not different to WT mice, and this was not further modified by in vivo blockade of IL-6 signalling. Consistent with reports of cognitive deficits associated with loss of neuronal dystrophin, the molecular correlate of memory formation, LTP, is decreased in mdx hippocampal slices relative to WT comparators. Local changes in pro-inflammatory mediators, linked to loss of dystrophin could underlie changes in hippocampal function, and indeed, blocking IL-6 receptors normalised LTP evoked in mdx mice. Although recognition memory was not changed by this intervention, our findings support a role for IL-6 in deficiencies in hippocampal function in dystrophin-deficient mdx mice at a cellular level. 1. Snow WM, Anderson JE, Jakobson LS. Neuropsychological and neurobehavioral functioning in Duchenne muscular dystrophy: a review. Neurosci Biobehav Rev.2013;37(5):743-52. 2. Gruol DL. IL-6 regulation of synaptic function in the CNS. Neuropharmacology. 2015;96(Pt A):42-54. 3. Vaillend C, Billard JM, Laroche S. Impaired long-term spatial and recognition memory and enhanced CA1 hippocampal LTP in the dystrophin-deficient Dmd(mdx) mouse. Neurobiol Dis. 2004;17(1):10-20.

The Immediate Early Gene Arc Is Not Required for Hippocampal Long-Term Potentiation.

Memory consolidation is thought to occur through protein synthesis-dependent synaptic plasticity mechanisms such as long-term potentiation (LTP). Dynamic changes in gene expression and epigenetic modifications underlie the maintenance of LTP. Similar mechanisms may mediate the storage of memory. Key plasticity genes, such as the immediate early gene Arc, are induced by learning and by LTP induction. Mice that lack Arc have severe deficits in memory consolidation, and Arc has been implicated in numerous other forms of synaptic plasticity, including long-term depression and cell-to-cell signaling. Here, we take a comprehensive approach to determine if Arc is necessary for hippocampal LTP in male and female mice. Using a variety of Arc knock-out (KO) lines, we found that germline Arc KO mice show no deficits in CA1 LTP induced by high-frequency stimulation and enhanced LTP induced by theta-burst stimulation. Temporally restricting the removal of Arc to adult animals and spatially restricting it to the CA1 using Arc conditional KO mice did not have an effect on any form of LTP. Similarly, acute application of Arc antisense oligodeoxynucleotides had no effect on hippocampal CA1 LTP. Finally, the maintenance of in vivo LTP in the dentate gyrus of Arc KO mice was normal. We conclude that Arc is not necessary for hippocampal LTP and may mediate memory consolidation through alternative mechanisms.SIGNIFICANCE STATEMENT The immediate early gene Arc is critical for maintenance of long-term memory. How Arc mediates this process remains unclear, but it has been proposed to sustain Hebbian synaptic potentiation, which is a key component of memory encoding. This form of plasticity is modeled experimentally by induction of LTP, which increases Arc mRNA and protein expression. However, mechanistic data implicates Arc in the endocytosis of AMPA-type glutamate receptors and the weakening of synapses. Here, we took a comprehensive approach to determine if Arc is necessary for hippocampal LTP. We find that Arc is not required for LTP maintenance and may regulate memory storage through alternative mechanisms.

Inhibitory Neural Network's Impairments at Hippocampal CA1 LTP in an Aged Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a rapid accumulation of amyloid β (Aβ) protein in the hippocampus, which impairs synaptic structures and neuronal signal transmission, induces neuronal loss, and diminishes memory and cognitive functions. The present study investigated the impact of neuregulin 1 (NRG1)-ErbB4 signaling on the impairment of neural networks underlying hippocampal long-term potentiation (LTP) in 5xFAD mice, a model of AD with greater symptom severity than that of TG2576 mice. Specifically, we observed parvalbumin (PV)-containing hippocampal interneurons, the effect of NRG1 on hippocampal LTP, and the functioning of learning and memory. We found a significant decrease in the number of PV interneurons in 11-month-old 5xFAD mice. Moreover, synaptic transmission in the 5xFAD mice decreased at 6 months of age. The 11-month-old transgenic AD mice showed fewer inhibitory PV neurons and impaired NRG1-ErbB4 signaling than did wild-type mice, indicating that the former exhibit the impairment of neuronal networks underlying LTP in the hippocampal Schaffer-collateral pathway. In conclusion, this study confirmed the impaired LTP in 5xFAD mice and its association with aberrant NRG1-ErbB signaling in the neuronal network.

Oligomer β-amyloid Induces Hyperactivation of Ras to Impede NMDA Receptor-Dependent Long-Term Potentiation in Hippocampal CA1 of Mice.

The activity of Ras, a small GTPase protein, is increased in brains with Alzheimer’s disease. The objective of this study was to determine the influence of oligomeric Aβ1-42 on the activation of Ras, and the involvement of the Ras hyperactivity in Aβ1-42-induced deficits in spatial cognition and hippocampal synaptic plasticity. Herein, we show that intracerebroventricular injection of Aβ1-42 in mice (Aβ-mice) enhanced hippocampal Ras activation and expression, while 60 min incubation of hippocampal slices in Aβ1-42 (Aβ-slices) only elevated Ras activity. Aβ-mice showed deficits in spatial cognition and NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) in hippocampal CA1, but basal synaptic transmission was enhanced. The above effects of Aβ1-42 were corrected by the Ras inhibitor farnesylthiosalicylic acid (FTS). ERK2 phosphorylation increased, and Src phosphorylation decreased in Aβ-mice and Aβ1-42-slices. Both were corrected by FTS. In CA1 pyramidal cells of Aβ1-42-slices, the response of AMPA receptor and phosphorylation of GluR1 were enhanced with dependence on Ras activation rather than ERK signaling. In contrast, NMDA receptor (NMDAR) function and GluN2A/2B phosphorylation were downregulated in Aβ1-42-slices, which was recovered by application of FTS or the Src activator ouabain, and mimicked in control slices treated with the Src inhibitor PP2. The administration of PP2 impaired the spatial cognition and LTP induction in control mice and FTS-treated Aβ-mice. The treatment of Aβ-mice with ouabain rescued Aβ-impaired spatial cognition and LTP. Overall, the results indicate that the oligomeric Aβ1-42 hyperactivates Ras and thereby causes the downregulation of Src which impedes NMDAR-dependent LTP induction resulting in cognitive deficits.

Acute Administration of Methyleugenol Impairs Hippocampus-Dependent Contextual Fear Memory and Increases Anxiety-like Behavior in Mice.

Methyleugenol (ME) as a natural essential oil in many plant species is widely used in human food and beverage for its fragrance and possible beneficial health effects. Previous chronic or subacute studies in rodents show that ME mainly causes liver toxicity. However, whether and how acute ME affects the central nervous system still remain elusive. Here, we found that ME administrated into the hippocampus impaired the acquisition of hippocampus-dependent contextual fear memory in mice (ME vs control: repeated-measures two-way ANOVA, F(5,70) = 2.937, p < 0.05; Fisher test, p < 0.05, respectively, 53 ± 5.2% vs 73 ± 7.6% during trial 4 and 46.8 ± 6% vs 74.5 ± 9.3% during trial 5). Meanwhile, acute ME impaired hippocampal CA1 long-term potentiation (LTP; ME vs control: independent t-test, p < 0.01, 110.6 ± 1.8% vs 133.3 ± 5.6%) while facilitated long-term depression (LTD; p < 0.01, 75.7 ± 3.4% vs 88.6 ± 1.7%) in mice brain slices and inducing a decrease in learning-dependent phosphorylation of Ser831 (ME vs control: independent t-test, p < 0.001, 0.87 ± 0.03 vs 1.23 ± 0.03) and Ser845 (p < 0.01, 0.42 ± 0.07 vs 0.97 ± 0.14) sites of excitatory glutamate AMPA receptor subunit 1 (GluA1) in the hippocampus, which may be the underlying mechanisms of impairment of hippocampus-dependent learning. In addition, intrahippocampal infusion of ME also increased anxiety-like behaviors in mice. These results suggested that acute ME impaired the hippocampus function at behavioral, cellular, and molecular levels, indicating the potential risks of ME on the central nervous system.

A Unique Mouse Model of Early Life Exercise Enables Hippocampal Memory and Synaptic Plasticity

Physical exercise is a powerful modulator of learning and memory. Mechanisms underlying the cognitive benefits of exercise are well documented in adult rodents. Exercise studies targeting postnatal periods of hippocampal maturation (specifically targeting periods of synaptic reorganization and plasticity) are lacking. We characterize a model of early-life exercise (ELE) in male and female mice designed with the goal of identifying critical periods by which exercise may have a lasting impact on hippocampal memory and synaptic plasticity. Mice freely accessed a running wheel during three postnatal periods: the 4th postnatal week (juvenile ELE, P21–27), 6th postnatal week (adolescent ELE, P35–41), or 4th-6th postnatal weeks (juvenile-adolescent ELE, P21–41). All exercise groups increased their running distances during ELE. When exposed to a subthreshold learning stimulus, juv ELE and juv-adol ELE formed lasting long-term memory for an object location memory task, whereas sedentary and adol ELE mice did not. Electrophysiological experiments revealed enhanced long-term potentiation in hippocampal CA1 in the juvenile-adolescent ELE group. I/O curves were also significantly modulated in all mice that underwent ELE. Our results suggest that early-life exercise, specifically during the 4th postnatal week, can enable hippocampal memory, synaptic plasticity, and alter hippocampal excitability when occurring during postnatal periods of hippocampal maturation.

TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common causes of neurodegenerative diseases in the elderly. The accumulation of amyloid‐β (Aβ) peptides is one of the pathological hallmarks of AD and leads to the impairments of synaptic plasticity and cognitive function. The transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel, is involved in synaptic plasticity and memory. However, the role of TRPV1 in AD pathogenesis remains largely elusive. Here, we reported that the expression of TRPV1 was decreased in the brain of APP23/PS45 double transgenic AD model mice. Genetic upregulation of TRPV1 by adeno‐associated virus (AAV) inhibited the APP processing and Aβ deposition in AD model mice. Meanwhile, upregulation of TRPV1 ameliorated the deficits of hippocampal CA1 long‐term potentiation (LTP) and spatial learning and memory through inhibiting GluA2‐containing α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) endocytosis. Furthermore, pharmacological activation of TRPV1 by capsaicin (1 mg/kg, i.p.), an agonist of TRPV1, dramatically reversed the impairments of hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, these results indicate that TRPV1 activation effectively ameliorates cognitive and synaptic functions through inhibiting AMPAR endocytosis in AD model mice and could be a novel molecule for AD treatment.

Transcriptome analysis of rat dorsal hippocampal CA1 after an early life seizure induced by kainic acid

Seizures that occur during early development are associated with adverse neurodevelopmental outcomes. Causation and mechanisms are currently under investigation. Induction of an early life seizure by kainic acid (KA) in immature rats on post-natal day (P) 7 results in behavioral changes in the adult rat that reflect social and intellectual deficits without overt cellular damage. Our previous work also demonstrated increased expression of CA1 hippocampal long-term potentiation (LTP) and reduced desensitization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic glutamate receptors (AMPA-R) one week following a kainic acid induced seizure (KA-ELS). Here we used RNA sequencing (RNAseq) of mRNA from dorsal hippocampal CA1 to probe changes in mRNA levels one week following KA-ELS as a means to investigate the mechanisms for these functional changes. Ingenuity pathway analysis (IPA) confirmed our previous results by predicting an up-regulation of the synaptic LTP pathway. Differential gene expression results revealed significant differences in 7 gene isoforms. Additional assessments included AMPA-R splice variants and adenosine deaminase acting on RNA 2 (ADAR2) editing sites as a means to determine the mechanism for reduced AMPA-R desensitization. Splice variant analysis demonstrated that KA-ELS result in a small, but significant decrease in the "flop" isoform of Gria3, and editing site analysis revealed significant changes in the editing of a kainate receptor subunit, Grik2, and a serotonin receptor, Htr2c. While these specific changes may not account for altered AMPA-R desensitization, the differences indicate that KA-ELS alters gene expression in the hippocampal CA1 one week after the insult.

P97 regulates GluA1 homomeric AMPA receptor formation and plasma membrane expression

The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs) mediate the fast excitatory synaptic transmission in the mammalian brain and are important for synaptic plasticity. In particular, the rapid insertion of the GluA1 homomeric (GluA1-homo) AMPARs into the postsynaptic membrane is considered to be critical in the expression of hippocampal CA1 long-term potentiation (LTP), which is important for certain forms of learning and memory. However, how the formation and trafficking of GluA1-homo AMPARs are regulated remains poorly understood. Here, we report that p97 specifically interacts with and promotes the formation of GluA1-homo AMPARs. The association with p97 retains GluA1-homo AMPARs in the intracellular compartment under basal conditions, and its dissociation allows GluA1-homo AMPARs to be rapidly inserted into the postsynaptic membrane shortly after LTP induction. Thus, our results shed lights into the molecular mechanisms by which p97 regulates GluA1-homo AMPARs formation and trafficking, thereby playing a critical role in mediating synaptic plasticity.

A TrkB agonist and ampakine rescue synaptic plasticity and multiple forms of memory in a mouse model of intellectual disability

Fragile X syndrome (FXS) is associated with deficits in various types of learning, including those that require the hippocampus. Relatedly, hippocampal long-term potentiation (LTP) is impaired in the Fmr1 knockout (KO) mouse model of FXS. Prior research found that infusion of brain-derived neurotrophic factor (BDNF) rescues LTP in the KOs. Here, we tested if, in Fmr1 KO mice, up-regulating BDNF production or treatment with an agonist for BDNF's TrkB receptor restores synaptic plasticity and improves learning. In hippocampal slices, bath infusion of the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) completely restored otherwise impaired hippocampal field CA1 LTP of Fmr1 KOs without effect in wild types (WTs). Similarly, acute, semi-chronic, or chronic treatments with 7,8-DHF rescued a simple hippocampus-dependent form of spatial learning (object location memory: OLM) in Fmr1 KOs without effect in WTs. The agonist also restored object recognition memory, which depends on cortical regions. Semi-chronic, but not acute, treatment with the ampakine CX929, which up-regulates BDNF expression, lowered the training threshold for OLM in WT mice and rescued learning in the KOs. Positive results were also obtained in a test for social recognition. An mGluR5 antagonist did not improve learning. Quantification of synaptic immunolabeling demonstrated that 7,8-DHF and CX929 increase levels of activated TrkB at excitatory synapses. Moreover, CX929 induced a robust synaptic activation of the TrkB effector ERK1/2. These results suggest that enhanced synaptic BDNF signaling constitutes a plausible strategy for treating certain aspects of the cognitive disabilities associated with FXS.

CA1 LTP Attenuated by Corticosterone is Canceled by Effusol via Rescuing Intracellular Zn2+ Dysregulation.

Exposure to corticosterone attenuates hippocampal CA1 long-term potentiation (LTP) via intracellular Zn2+ dysregulation. Here we report that effusol, a phenanthrene isolated from Chinese medicine Juncus effusus, rescues CA1 LTP attenuated by corticosterone. In vivo microdialysis experiment indicated that both increases in extracellular glutamate induced under perfusion with corticosterone and high K+ are suppressed in the hippocampus by co-perfusion with effusol. Because corticosterone and high K+ also increase extracellular Zn2+ level, followed by intracellular Zn2+ dysregulation, the effect of effusol on both the increases was examined in brain slice experiments. Effusol did not suppress increase in extracellular Zn2+ in the hippocampal CA1 of brain slices bathed in corticosterone, but suppressed increase in intracellular Zn2+, which may be linked with suppressing the increase in extracellular glutamate in vivo. In vivo CA1 LTP was attenuated under perfusion with corticosterone prior to LTP induction, while the attenuation was rescued by co-perfusion with effusol, suggesting that the rescuing effect of effusol is due to suppressing the increase in intracellular Zn2+ in CA1 pyramidal cells. The present study indicates that CA1 LTP attenuated by corticosterone is canceled by effusol, which rescues intracellular Zn2+ dysregulation via suppressing extracellular glutamate accumulation. It is likely that effusol defends the hippocampal function against stress-induced cognitive decline.