SerpinA3N deficiency deteriorates impairments of learning and memory in mice following hippocampal stab injury.
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ABSTRACT:
SUBMITTER: Wang ZM
PROVIDER: S-EPMC7501238 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The hippocampus is vital for functions such as mood and memory. Hippocampal injury typically leads to mood and memory impairments associated with reduced and aberrant neurogenesis in the dentate gyrus. We examined whether neural stem cell (NSC) grafting after hippocampal injury would counteract impairments in mood, memory, and neurogenesis. We expanded NSCs from the anterior subventricular zone (SVZ) of postnatal F344 rat pups expressing the human placental alkaline phosphatase and grafted them into the hippocampus of young adult F344 rats at 5 days after an injury inflicted through a unilateral intracerebroventricular administration of kainic acid. Analyses through forced swim, water maze, and novel object recognition tests revealed significant impairments in mood and memory function in animals that underwent injury and sham-grafting surgery. In contrast, animals that received SVZ-NSC grafts after injury exhibited mood and memory function comparable to those of naïve control animals. Graft-derived cells exhibited excellent survival and pervasive migration, and they differentiated into neurons, subtypes of inhibitory GABAergic interneurons, astrocytes, oligodendrocytes, and oligodendrocyte progenitors. Significant fractions of graft-derived cells also expressed beneficial neurotrophic factors such as the glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, fibroblast growth factor, and vascular endothelial growth factor. Furthermore, SVZ-NSC grafting counteracted the injury-induced reductions and abnormalities in neurogenesis by both maintaining a normal level of NSC activity in the subgranular zone and providing protection to reelin+ interneurons in the dentate gyrus. These results underscore that early SVZ-NSC grafting intervention after hippocampal injury is efficacious for thwarting mood and memory dysfunction and abnormal neurogenesis.
| S-EPMC3612501 | biostudies-literature
Project description:IntroductionPrevious research indicates disruption of learning and memory in children who have experienced traumatic brain injury (TBI).ObjectiveThis research evaluates the impact of pediatric TBI on volumetric differences along the long axis of the hippocampus, a region of the brain that is critical for explicit memory.MethodsStructural brain data and behavioral measures were collected 6 weeks following TBI or extracranial injury (EI), in children aged 8-15 years and from a group of age matched typically developing controls (TDC). Total hippocampal volume and hippocampal subregion volumes corresponding to hippocampal head, body, and tail were compared across groups and were examined in relation to verbal and visual memory.ResultsGroup differences were evident such that hippocampal body volume was found to be smaller for TBI and EI groups compared to the TDC group. Analysis restricted to the TBI group indicated that hippocampal head volume was associated with severity of injury. The relation between severity of injury and hippocampal head volume is particularly important considering results from our investigation of hippocampal volume-to-memory performance relations indicating positive correlations between hippocampal head volume and performance on memory measures for both the TBI group and the TDC group. Significant negative correlations between hippocampal body volume and memory were evident for the TBI group but not EI or TDC groups. Correlations between memory performance and hippocampal tail volume were not significant for the TBI or TDC groups, although for the EI group, a positive correlation was found between hippocampal tail volume and memory.ConclusionTogether these results underscore an important relation between hippocampal structure and memory function during the subacute stage of recovery from pediatric TBI.
| S-EPMC5745237 | biostudies-literature
Project description:BACKGROUND:Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of (S)-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs. The knockdown of PKD1 does not affect the DHPG-induced inhibition of AMPA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs) but prevents the DHPG-induced inhibition of NMDAR-mediated mEPSCs in vitro. Thus, we investigated the in vivo effects of bilateral infusions of DHPG into the hippocampal CA1 area of rats in the Morris water maze (MWM) and the novel object discrimination (NOD) tests. METHODS:A total of 300 adult male Sprague Dawley rats (250-280 g) were used for behavioral tests. One hundred ninety four were used in MWM test and the other 106 rats in the NOD test. Following one week of habituation to the vivarium, rats were bilaterally implanted under deep anesthesia with cannulas aimed at the CA1 area of the hippocampus (CA1 coordinates in mm from Bregma: AP -3.14; lateral +/-2; DV -3.0). Through implanted cannulas artificial cerebrospinal fluid (ACSF), the group1 mGluR antagonist 6-Methyl-2-(phenylethynyl)pyridine (MPEP), the dynamin-dependent internalization inhibitor Dynasore, or the PKD1 inhibitor CID755673 were infused into the bilateral hippocampal CA1 areas (2 ?L per side, over 5 min). The effects of these infusions and the effects of PKD1 knockdown were examined in MWM or NOD test. RESULTS:DHPG infusion increased the latency to reach the platform in the MWM test and reduced the preference for the novel object in the NOD task. We found that the DHPG effects were dose-dependent and could be maintained for up to 2 days. Notably, these effects could be prevented by pre-infusion of the group1 mGluR antagonist MPEP, the dynamin-dependent internalization inhibitor Dynasore, the PKD1 inhibitor CID755673, or by PKD1 knockdown in the hippocampal CA1 area. CONCLUSION:Altogether, these findings provide direct evidence that PKD1-mediated signaling may play a critical role in the induction of learning and memory impairments by DHPG infusion into the hippocampal CA1 area.
| S-EPMC5882104 | biostudies-literature
Project description:Alzheimer's disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment. Hippocampal sharp-wave ripples (SWRs)-electrophysiological signatures of memory reactivation in the hippocampus-are a compelling candidate for this purpose. Mouse models of AD show reductions in both SWR abundance and associated slow gamma (SG) power during aging, but these alterations have yet to be directly linked to memory impairments. In aged apolipoprotein E4 knockin (apoE4-KI) mice-a model of the major genetic risk factor for AD-we find that reduced SWR abundance and associated CA3 SG power predicted spatial memory impairments measured 1-2 months later. Importantly, SWR-associated CA3 SG power reduction in young apoE4-KI mice also predicted spatial memory deficits measured 10 months later. These results establish features of SWRs as potential functional biomarkers of memory impairment in AD.
| S-EPMC7437815 | biostudies-literature
Project description:A healthy mitochondrial network is essential for the maintenance of neuronal synaptic integrity. Mitochondrial and metabolic dysfunction contributes to the pathogenesis of many neurodegenerative diseases including dementia. OPA1 is the master regulator of mitochondrial fusion and fission and is likely to play an important role during neurodegenerative events. To explore this, we quantified hippocampal dendritic and synaptic integrity and the learning and memory performance of aged Opa1 haploinsufficient mice carrying the Opa1Q285X mutation (B6; C3-Opa1Q285STOP ; Opa1+/- ). We demonstrate that heterozygous loss of Opa1 results in premature age-related loss of spines in hippocampal pyramidal CA1 neurons and a reduction in synaptic density in the hippocampus. This loss is associated with subtle memory deficits in both spatial novelty and object recognition. We hypothesize that metabolic failure to maintain normal neuronal activity at the level of a single spine leads to premature age-related memory deficits. These results highlight the importance of mitochondrial homeostasis for maintenance of neuronal function during ageing.
| S-EPMC7566495 | biostudies-literature
Project description:(1) Background: Inducing experimental stroke leads to biphasic immune responses, where the early activation of immune functions is followed by severe immunosuppression accompanied by spleen and thymus atrophy. Nicotinamide, a water-soluble B-group vitamin, is a known neuroprotectant against brain ischemia in animal models. We examined the effect of nicotinamide on the central and peripheral immune response in experimental stroke models. (2) Methods: Nicotinamide (500 mg/kg) or saline was intravenously administered to C57BL/6 mice during reperfusion after transiently occluding the middle cerebral artery or after LPS injection. On day 3, the animals were examined for behavioral performance and were then sacrificed to assess brain infarction, blood–brain barrier (BBB) integrity, and the composition of immune cells in the brain, thymus, spleen, and blood using flow cytometry. (3) Results: Nicotinamide reduced brain infarction and microglia/macrophage activation following MCAo (p < 0.05). Similarly, in LPS-injected mice, microglia/macrophage activation was decreased upon treatment with nicotinamide (p < 0.05), suggesting a direct inhibitory effect of nicotinamide on microglia/macrophage activation. Nicotinamide decreased the infiltration of neutrophils into the brain parenchyma and ameliorated Evans blue leakage (p < 0.05), suggesting that a decreased infiltration of neutrophils could, at least partially, be the result of a more integrated BBB structure following nicotinamide treatment. Our studies also revealed that administering nicotinamide led to retarded B-cell maturation in the spleen and subsequently decreased circulating B cells in the thymus and bloodstream (p < 0.05). (4) Conclusions: Cumulatively, nicotinamide decreased brain inflammation caused by ischemia–reperfusion injury, which was mediated by a direct anti-inflammatory effect of nicotinamide and an indirect protective effect on BBB integrity. Administering nicotinamide following brain ischemia resulted in a decrease in circulating B cells. This warrants attention with respect to future clinical applications.
| S-EPMC10452067 | biostudies-literature
Project description:Neurotropic viruses target the brain and contribute to neurologic diseases. Caspase recruitment domain containing family member 9 (CARD9) controls protective immunity in a variety of infectious disorders. To investigate the effect of CARD9 in neurotropic virus infection, CARD9-/- and corresponding C57BL/6 wild-type control mice were infected with Theiler's murine encephalomyelitis virus (TMEV). Brain tissue was analyzed by histology, immunohistochemistry and molecular analyses, and spleens by flow cytometry. To determine the impact of CARD9 deficiency on T cell responses in vitro, antigen presentation assays were utilized. Genetic ablation of CARD9 enhanced early pro-inflammatory cytokine responses and accelerated infiltration of T and B cells in the brain, together with a transient increase in TMEV-infected cells in the hippocampus. CARD9-/- mice showed an increased loss of neuronal nuclear protein+ mature neurons and doublecortin+ neuronal precursor cells and an increase in β-amyloid precursor protein+ damaged axons in the hippocampus. No effect of CARD9 deficiency was found on the initiation of CD8+ T cell responses by flow cytometry and co-culture experiments using virus-exposed dendritic cells or microglia-enriched glial cell mixtures, respectively. The present study indicates that CARD9 is dispensable for the initiation of early antiviral responses and TMEV elimination but may contribute to the modulation of neuroinflammation, thereby reducing hippocampal injury following neurotropic virus infection.
| S-EPMC8268812 | biostudies-literature
Project description:N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammalian messenger RNAs (mRNAs). While m6A has been shown to mark groups of mRNAs for coordinated degradation in various physiological processes, the relevance of m6A in affecting translation remains to be determined in intact biological systems in vivo. Here we show that, through its reader protein Ythdf1, m6A promotes a pulse of protein synthesis of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory processes. Mice with genetic deletion of the Ythdf1 gene (Ythdf1-/-) exhibit learning and memory defects, as well as impaired hippocampal synaptic transmission and long-term potentiation (LTP). Selective re-expression of Ythdf1 in the hippocampus of adult Ythdf1-/- mice fully rescues the behavioral and synaptic defects, while hippocampus-specific knockdown of Ythdf1 or Mettl3, the catalytic component of m6A methyltransferase complex, recapitulates the hippocampal deficiency in adult mice. At the molecular level, transcriptome-wide mapping of m6A sites and RNA binding sites of Ythdf1 on hippocampal mRNAs using crosslinking immunoprecipitation followed by high-throughput sequencing (CLIP-seq) uncovered key neuronal genes, including those involved in synaptic transmission and long-term potentiation. Nascent protein labelling and tether reporter assays in cultured hippocampal neurons revealed that Ythdf1 is critical for initiating a pulse of protein synthesis of target transcripts in a neuronal-stimulus-dependent manner. Collectively, our results uncover a pathway of mRNA m6A methylation in learning and memory, which is mediated through Ythdf1 in response to stimuli.
2018-08-17 | GSE106607 | GEO
Project description:Abnormal accumulation of hyperphosphorylated tau induces pathogenesis in neurodegenerative diseases, like Alzheimer's disease. Molecular chaperones with peptidyl-prolyl cis/trans isomerase (PPIase) activity are known to regulate these processes. Previously, in vitro studies have shown that the 52 kDa FK506-binding protein (FKBP52) interacts with tau inducing its oligomerization and fibril formation to promote toxicity. Thus, we hypothesized that increased expression of FKBP52 in the brains of tau transgenic mice would alter tau phosphorylation and neurofibrillary tangle formation ultimately leading to memory impairments. To test this, tau transgenic (rTg4510) and wild-type mice received bilateral hippocampal injections of virus overexpressing FKBP52 or GFP control. We examined hippocampal-dependent memory, synaptic plasticity, tau phosphorylation status, and neuronal health. This work revealed that rTg4510 mice overexpressing FKBP52 had impaired spatial learning, accompanied by long-term potentiation deficits and hippocampal neuronal loss, which was associated with a modest increase in total caspase 12. Together with previous studies, our findings suggest that FKBP52 may sensitize neurons to tau-mediated dysfunction via activation of a caspase-dependent pathway, contributing to memory and learning impairments.
| S-EPMC8093247 | biostudies-literature
Project description:We hypothesized that mouse Brpf1 plays critical roles in the morphology and function of hippocampal neurons, and its deficiency leads to learning and memory deficits. To test this, we performed immunofluorescence, whole-cell patch clamp, mRNA-Seq on shBrpf1 infected primary cultured hippocampal neurons to study the effect of Brpf1 knockdown on neuronal morphology, electrophysiological characteristics and gene regulation. In addition, we performed stereotactic injection into adult mouse hippocampus to knockdown Brpf1 in vivo and examined the learning and memory ability by Morris Water Maze. We found that mild knockdown of Brpf1 reduced mEPSC frequency of cultured hippocampal neurons, before any significant changes of dendritic morphology showed. We also found that hippocampal knockdown of Brpf1 reduced the learning and memory ability of mice to some extent. Finally, mRNA-Seq analyses showed that genes related to learning, memory, movement and synaptic transmission (such as C1ql1, Gpr17, Htr1d, Glra1, Cxcl10, Grin2a) were dysregulated upon Brpf1 knockdown. Our results showed that Brpf1 mild knockdown attenuated hippocampal excitatory neurotransmission and reduced learning and memory ability, which helps explain the symptoms of patients with BRPF1 mutations.
2021-05-19 | GSE174600 | GEO