The ataxic Cacna1a-mutant mouse rolling nagoya: an overview of neuromorphological and electrophysiological findings.
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ABSTRACT:
SUBMITTER: Plomp JJ
PROVIDER: S-EPMC2734259 | biostudies-other | 2009 Sep
REPOSITORIES: biostudies-other
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Project description:AIMS:MeCP2 gene mutations are associated with Rett syndrome and X-linked mental retardation (XLMR), diseases characterized by abnormal brain development and function. Recently, we created a novel MeCP2 A140V mutation mouse model that exhibited abnormalities of cell packing density and dendritic branching consistent with that seen in Rett syndrome patients as well as other MeCP2 mutant mouse models. Therefore, we hypothesized that some deficits of neuronal and synaptic functions might also be present in the A140V mutant model. METHODS:Here, we tested our hypothesis in hippocampal slices using electrophysiological recordings. RESULTS:We found that in young A140V mutant mice (3- to 4-week-old), hippocampal CA1 pyramidal neurons exhibited more positive resting membrane potential, increased action potential (AP) firing frequency induced by injection of depolarizing current, wider AP duration, and smaller after hyperpolarization potential compared to neurons prepared from age-matched wild-type mice, suggesting a neuronal hyperexcitation. At the synaptic level, A140V mutant neurons exhibited a reduced frequency of spontaneous IPSCs (inhibitory postsynaptic potentials) and an enhanced probability of evoked glutamate release, both suggesting neuronal hyperexcitation. However, hippocampal CA1 long-term potentiation was not significantly different between A140V and WT mice. In adult mice (11- to 13-month-old), in addition to neuronal hyperexcitation, we also found significant deficits of both short-term and long-term potentiation of CA3-CA1 synapses in A140V mice compared to WT mice. CONCLUSIONS:These results clearly illustrate the age-dependent abnormalities of neuronal and synaptic function in the MeCP2 A140V mutant mouse model, which provides new insights into the understanding of the pathogenesis of Rett syndrome.
| S-EPMC6493136 | biostudies-literature
Project description:BackgroundThe Neuregulin 1 transmembrane domain heterozygous mutant (Nrg1 TM HET) mouse is used to investigate the role of Nrg1 in brain function and schizophrenia-like behavioural phenotypes. However, the molecular alterations in brain Nrg1 expression that underpin the behavioural observations have been assumed, but not directly determined. Here we comprehensively characterise mRNA Nrg1 transcripts throughout development of the Nrg1 TM HET mouse. In addition, we investigate the regulation of high-frequency (gamma) electrophysiological oscillations in this mutant mouse to associate molecular changes in Nrg1 with a schizophrenia-relevant neurophysiological profile.MethodsUsing exonic probes spanning the cysteine-rich, epidermal growth factor (EGF)-like, transmembrane and intracellular domain encoding regions of Nrg1, mRNA levels were measured using qPCR in hippocampus and frontal cortex from male and female Nrg1 TM HET and wild type-like (WT) mice throughout development. We also performed electrophysiological recordings in adult mice and analysed gamma oscillatory at baseline, in responses to auditory stimuli and to ketamine.ResultsIn both hippocampus and cortex, Nrg1 TM HET mice show significantly reduced expression of the exon encoding the transmembrane domain of Nrg1 compared with WT, but unaltered mRNA expression encoding the extracellular bioactive EGF-like and the cysteine-rich (type III) domains, and development-specific and region-specific reductions in the mRNA encoding the intracellular domain. Hippocampal Nrg1 protein expression was not altered, but NMDA receptor NR2B subunit phosphorylation was lower in Nrg1 TM HET mice. We identified elevated ongoing and reduced sensory-evoked gamma power in Nrg1 TM HET mice.InterpretationWe found no evidence to support the claim that the Nrg1 TM HET mouse represents a simple haploinsufficient model. Further research is required to explore the possibility that mutation results in a gain of Nrg1 function.
| S-EPMC4437646 | biostudies-literature
Project description:ObjectiveThe pathogenesis of hearing loss in autoinflammatory disorders due to activation of the inflammasome remains incompletely understood. Previously no animals expressing mutant Nlrp3 (NOD-, LRR- and pyrin domain-containing protein 3) survived to an age when hearing evaluation was possible due to embryonic lethality. We aimed to establish a novel mouse model that manifests quantifiable hearing loss with other syndromic features due to alteration of Nlrp3 and investigate the audiologic and histopathologic phenotype in the cochlea to clarify how the genetic alterations of NLRP3 could induce autoinflammatory hearing loss.MethodsTo induce inner ear expression of the mutant Nlrp3, Nlrp3 D301NneoR mice were bred with Gfi1 Cre knock-in mice for conditional mutant Nlrp3 activation in the cochlea and hematopoietic cells. Hearing thresholds were measured. Hematoxylin-eosin sections of the cochlea, brain, kidney, and liver were examined under light microscopy. Immunohistochemical analyses using polyclonal anti-NLRP3 antibodies on cochlear whole-mount preparations and frozen sections were performed.ResultsWe, for the first time in the literature, established a mouse model that manifests quantifiable hearing loss due to Nlrp3 alteration. ABR recordings of Nlrp3 D301NneoR/+; Gfi1 Cre/+ mice, albeit with limited life expectancy, exhibited severe to profound hearing loss at postnatal day 20 (P20). There was overall overexpression of mutant Nlrp3, and mutant Nlrp3 expression was noted in the spiral prominence, the outer sulcus region (Claudius cells and outer sulcus cells), the organ of Corti, the inner sulcus, and the spiral ganglion neurons in the cochlea. The hematoxylin-eosin sections of Nlrp3 D301NneoR/+; Gfi1 Cre/+ mice cochleae at P12 exhibited a disorganized organ of Corti between the outer hair cells/supporting Deiters' cells and basilar membrane compared with the normal phenotype mice, leading to a collapsed Nuel's space. This morphologic feature gradually returned to normal by P15. Varying degrees of inflammation with lymphocytic infiltrations were observed in the brain, kidney, and liver.ConclusionWe report the first mutant Nlrp3 overexpression mouse model (Nlrp3 D301NneoR/+; Gfi1 Cre/+) that shows obvious overexpression of Nlrp3 in the cochlea, a transient developmental lag of the cochlea, and severe to profound hearing loss. We expect that this mouse line, which models human autoinflammatory hearing loss, could provide a valuable tool to elucidate the underlying pathogenic mechanism of inflammasome activation-mediated hearing loss.
| S-EPMC9263128 | biostudies-literature
Project description:We aimed to investigate changes in electrophysiological findings in Turkish patients with restless legs syndrome (RLS), including F-wave latency (FWL), peripheral silent period (PSP), and Hoffmann reflex. The study took place in a university hospital in Turkey and involved 30 newly diagnosed RLS patients and 30 healthy controls who were matched for age and gender. Participant's demographics (age, gender, weight, and height), laboratory findings, and electrophysiological test outcomes were gathered and analyzed. There was no significant difference in the FWL of the median and ulnar nerves, whereas the H-wave maximum amplitude and H/M ratio were significantly higher in the RLS patients than in the controls at rest. All of the PSP parameters were similar between patients and controls for the abductor pollicis brevis and gastrocnemius muscles. However, for the tibialis anterior muscle, all the PSP duration parameters were shorter in the RLS patients, whereas the PSP latency parameters were similar. The data suggest that there may be a reduction in spinal segmental inhibition at the L4-L5-S1 level, but the mechanisms of inhibition at the L4-L5 and S1 levels may be different; furthermore, there may be no pathology in the peripheral nerves. Further prospective studies with larger cohorts are now needed to evaluate the pathophysiology of RLS with different neurophysiological assessment tools.
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Project description:Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE) since it is the major predictor of poor prognosis. In susceptible individuals suffering of SLE, in situ formation and deposit of immune complexes (ICs) from apoptotic bodies occur in the kidneys as a result of an amplified epitope immunological response. IC glomerular deposits generate release of proinflammatory cytokines and cell adhesion molecules causing inflammation. This leads to monocytes and polymorphonuclear cells chemotaxis. Subsequent release of proteases generates endothelial injury and mesangial proliferation. Presence of ICs promotes adaptive immune response and causes dendritic cells to release type I interferon. This induces maturation and activation of infiltrating T cells, and amplification of Th2, Th1 and Th17 lymphocytes. Each of them, amplify B cells and activates macrophages to release more proinflammatory molecules, generating effector cells that cannot be modulated promoting kidney epithelial proliferation and fibrosis. Herein immunopathological findings of LN are reviewed.
| S-EPMC3318208 | biostudies-literature
Project description:BackgroundNeuroelectrophysiological measures such as electroencephalograms (EEGs) in resting state and event-related potentials (ERPs) provide valuable information about the vulnerability and treatment-related changes in persons with alcoholism. This study examined the effectiveness of an Integrated Intervention Program for Alcoholism (IIPA) using electrophysiological measures.MethodsFifty individuals with early onset of alcohol dependence participated. They were grouped randomly into two: the treatment as usual (TAU) group and the treatment group, matched on age (±1 year) and education (±1 year). eyes closed and resting state EEGs and ERPs on cognitive tasks (flanker task, alcohol Go/No-Go task, and single outcome gambling task) were recorded before and after treatment. The TAU group received pharmacotherapy, six days/week yoga sessions, and three sessions/week group therapy on relapse prevention while the treatment group received IIPA along with usual treatment (except yoga) for 18 days.ResultsThere was no significant difference between the groups pre-treatment. RM-ANOVA for pre- and post-treatment stages showed a significant difference between the two groups in the absolute power of alpha, beta, theta, and delta, during eye closure, in the resting-state EEGs. The treatment group showed significantly larger N200/N2 amplitude in congruent and incongruent conditions (flanker task), N200/N2 amplitude for alcohol No-Go, P300/P3 amplitude for neutral No-Go on alcohol Go/No-Go task, and outcome-related positivity (ORP) amplitude on single outcome gambling task.ConclusionThis exploratory study suggests that IIPA is effective for enhancing relaxation state and attentiveness, decreasing hyperarousal, and ameliorating neurocognitive dysfunctions of conflict-monitoring, response inhibition, and reward processing.
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Project description:AimTo assess the prognostic capabilities of various diagnostic modalities for childhood brachial plexus injuries (BPIs) and brachial plexus birth injury (BPBI) and postneonatal BPI.MethodIn this single-center retrospective cross-sectional study, we examined children with BPIs diagnosed or confirmed by electrodiagnostic studies between 2013 and 2020, and compared the prognostic value of various components of the electrophysiologic findings, magnetic resonance imaging (MRI) data, and the Active Movement Scale (AMS). We developed scoring systems for electrodiagnostic studies and MRI findings, including various components of nerve conduction studies and electromyography (EMG) for electrodiagnostic studies.ResultsWe identified 21 children (10 females and 11 males) aged 8 days to 21 years (mean 8y 6.95mo) who had a total of 30 electrodiagnostic studies, 14 brachial plexus MRI studies, and 10 surgical procedures. Among the diagnostic modalities assessed, brachial plexus MRI scores, EMG denervation scores, and mean total EMG scores were the most valuable in predicting surgical versus non-surgical outcomes. Correspondingly, a combined MRI/mean total EMG score provided prognostic value.InterpretationBrachial plexus MRI scores and specific electrodiagnostic scores provide the most accurate prognostic information for children with BPI. Our grading scales can assist a multidisciplinary team in quantifying results of these studies and determining prognosis in this setting.What this paper addsA new scoring system to quantify results of electrodiagnostic and magnetic resonance imaging (MRI) studies is presented. Severity of denervation has good prognostic value for childhood brachial plexus injuries (BPIs). Composite electromyography scores have good prognostic value for childhood BPIs. Brachial plexus MRI has good prognostic value for childhood BPIs.
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Project description:Genetics constitute a crucial risk factor to schizophrenia. In the last decade, molecular genetic research has produced novel findings, infusing optimism about discovering the biological roots of schizophrenia. However, the complexity of the object of inquiry makes it almost impossible for non-specialists in genetics (e.g., many clinicians and researchers) to get a proper understanding and appreciation of the genetic findings and their limitations. This study aims at facilitating such an understanding by providing a brief overview of some of the central methods and findings in schizophrenia genetics, from its historical origins to its current status, and also by addressing some limitations and challenges that confront this field of research. In short, the genetic architecture of schizophrenia has proven to be highly complex, heterogeneous and polygenic. The disease risk is constituted by numerous common genetic variants of only very small individual effect and by rare, highly penetrant genetic variants of larger effects. In spite of recent advances in molecular genetics, our knowledge of the etiopathogenesis of schizophrenia and the genotype-environment interactions remain limited.
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Project description:Lennox-Gastaut syndrome (LGS) is a rare, age-related syndrome, characterized by multiple seizure types, a specific electro-encephalographic pattern, and mental regression. However, published data on the etiology, evolution, and therapeutic approach of LGS are contradictory, partly because the precise definition of LGS used in the literature varies. In the most recent classification, LGS belongs to the epileptic encephalopathies and is highly refractory to all antiepileptic drugs. Numerous treatments, medical and non-medical, have been proposed and results mostly from open studies or case series have been published. Sometimes, patients with LGS are included in a more global group of patients with refractory epilepsy. Only 6 randomized double-blind controlled trials of medical treatments, which included patients with LGS, have been published. Overall, treatment is rarely effective and the final prognosis remains poor in spite of new therapeutic strategies. Co-morbidities need specific treatment. This paper summarizes the definition, diagnosis and therapeutic approach to LGS, including not only recognized antiepileptic drugs, but also "off label" medications, immune therapy, diet, surgery and some perspectives for the future.
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Project description:With the successful completion of genomic sequencing for Brassica napus, identification of novel genes, determination of functions performed by genes, and exploring the molecular mechanisms underlying important agronomic traits were challenged. Mutagenesis-based functional genomics techniques including chemical, physical, and insertional mutagenesis have been used successfully in the functional characterization of genes. However, these techniques had their disadvantages and inherent limitations for allopolyploid Brassica napus, which contained a large number of homologous and redundant genes. Long intron-spliced hairpin RNA (ihpRNA) constructs which contained inverted repeats of the target gene separated by an intron, had been shown to be very effective in triggering RNAi in plants. In the present study, the genome-wide long ihpRNA library of B. napus was constructed with the rolling circle amplification (RCA)-mediated technology. Using the phytoene desaturase (PDS) gene as a target control, it was shown that the RCA-mediated long ihpRNA construct was significantly effective in triggering gene silence in B. napus. Subsequently, the resultant long ihpRNA library was transformed into B. napus to produce corresponding RNAi mutants. Among the obtained transgenic ihpRNA population of B. napus, five ihpRNA lines with observable mutant phenotypes were acquired including alterations in the floral model and the stamen development. The target genes could be quickly identified using specific primers. These results showed that the RCA-mediated ihpRNA construction method was effective for the genome-wide long ihpRNA library of B. napus, therefore providing a platform for study of functional genomics in allopolyploid B. napus.
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