Gad1 knock-out rats exhibit abundant spike-wave discharges in EEG, exacerbated with valproate treatment
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ABSTRACT:
SUBMITTER: Liu D
PROVIDER: S-EPMC10566305 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Intraflagellar transport (IFT) is a bidirectional transport process that occurs along primary cilia and specialized sensory cilia, such as photoreceptor outersegments. Genes coding for various IFT components are associated with ciliopathies. Mutations in IFT172 lead to diseases ranging from isolated retinal degeneration to severe syndromic ciliopathies. In this study, we created a mouse model of IFT172-associated retinal degeneration to investigate the ocular disease mechanism. We found that depletion of IFT172 in rod photoreceptors leads to a rapid degeneration of the retina, with severely reduced electroretinography (ERG) responses by 1 month and complete outer-nuclear layer (ONL) degeneration by 2 months. We investigated molecular mechanisms of degeneration and show that IFT172 protein reduction leads to mislocalization of specific photoreceptor outersegment (OS) proteins (RHO, RP1, IFT139), aberrant light-driven translocation of alpha transducin and altered localization of glioma-associated oncogene family member 1 (GLI1). This mouse model exhibits key features of the retinal phenotype observed in patients with IFT172-associated blindness and can be used for in vivo testing of ciliopathy therapies.
| S-EPMC5961092 | biostudies-literature
Project description:IntroductionDifferent studies have investigated by means of EEG-fMRI coregistration the brain networks related to generalized spike-and-wave discharges (GSWD) in patients with idiopathic generalized epilepsy (IGE). These studies revealed a widespread GSWD-related neural network that involves the thalamus and regions of the default mode network. In this study we investigated which brain regions are critically involved in the termination of absence seizures (AS) in a group of IGE patients.MethodsEighteen patients (6 male; mean age 25 years) with AS were included in the EEG-fMRI study. Functional data were acquired at 3T with continuous simultaneous video-EEG recording. Event-related analysis was performed with SPM8 software, using the following regressors: (1) GSWD onset and duration; (2) GSWD offset. Data were analyzed at single-subject and at group level with a second level random effect analysis.ResultsA mean of 17 events for patient was recorded (mean duration of 4.2 sec). Group-level analysis related to GSWD onset respect to rest confirmed previous findings revealing thalamic activation and a precuneus/posterior cingulate deactivation. At GSWD termination we observed a decrease in BOLD signal over the bilateral dorsolateral frontal cortex respect to the baseline (and respect to GSWD onset). The contrast GSWD offset versus onset showed a BOLD signal increase over the precuneus-posterior cingulate region bilaterally. Parametric correlations between electro-clinical variables and BOLD signal at GSWD offset did not reveal significant effects.ConclusionThe role of the decreased neural activity of lateral prefrontal cortex at GSWD termination deserve future investigations to ascertain if it has a role in promoting the discharge offset, as well as in the determination of the cognitive deficits often present in patients with AS. The increased BOLD signal at precuneal/posterior cingulate cortex might reflect the recovery of neural activity in regions that are "suspended" during spike and waves activity, as previously hypothesized.
| S-EPMC4496065 | biostudies-literature
Project description:Both CLN1 and CLN5 deficiency leads to severe neurodegenerative diseases of childhood, known as neuronal ceroid lipofuscinoses (NCL). The broadly similar phenotypes of NCL mouse models, and the potential for interactions between NCL proteins, raise the possibility of shared or converging disease mechanisms. To begin addressing these issues we have developed a novel mouse model lacking both Cln1 and Cln5 genes. These Cln1/5 double knock-out (Cln1/5 dko) mice were fertile, showing a slight decrease in expected Mendelian breeding ratios, as well as impaired embryoid body formation of induced pluripotent stem cells derived from Cln1/5 dko fibroblasts. Typical manifestations of the NCL diseases, seizures and motor dysfunction, were detected at the age of 3 months, earlier than in either single knock-out mouse. Pathological analyses revealed a similar exacerbation and earlier onset of disease in Cln1/5 dko mice, which exhibit a pronounced accumulation of autofluorescent storage material. Cortical demyelination and more pronounced glial activation in cortical and thalamic regions was followed by cortical neuron loss. Alterations in lipid metabolism in Cln1/5 dko showed specifically an increase in serum phospholipid transfer protein (PLTP) activity. Finally, gene expression profiling of Cln1/5 dko cortex revealed defects in myelination and immune response pathways, with a prominent downregulation of alpha-synuclein in Cln1/5 dko mouse brains. The simultaneous loss of both Cln1 and Cln5 genes may enhance the typical pathological phenotypes of these mice by disrupting down shared or convergent pathogenic pathways, which may potentially include interactions of CLN1 and CLN5.
2012-10-31 | GSE37643 | GEO
Project description:We will perform RNAseq to evaluate the effects of the loss of a list of TSGs on the transcriptome.
| EGAS00001002262 | EGA
Project description:Both CLN1 and CLN5 deficiency leads to severe neurodegenerative diseases of childhood, known as neuronal ceroid lipofuscinoses (NCL). The broadly similar phenotypes of NCL mouse models, and the potential for interactions between NCL proteins, raise the possibility of shared or converging disease mechanisms. To begin addressing these issues we have developed a novel mouse model lacking both Cln1 and Cln5 genes. These Cln1/5 double knock-out (Cln1/5 dko) mice were fertile, showing a slight decrease in expected Mendelian breeding ratios, as well as impaired embryoid body formation of induced pluripotent stem cells derived from Cln1/5 dko fibroblasts. Typical manifestations of the NCL diseases, seizures and motor dysfunction, were detected at the age of 3 months, earlier than in either single knock-out mouse. Pathological analyses revealed a similar exacerbation and earlier onset of disease in Cln1/5 dko mice, which exhibit a pronounced accumulation of autofluorescent storage material. Cortical demyelination and more pronounced glial activation in cortical and thalamic regions was followed by cortical neuron loss. Alterations in lipid metabolism in Cln1/5 dko showed specifically an increase in serum phospholipid transfer protein (PLTP) activity. Finally, gene expression profiling of Cln1/5 dko cortex revealed defects in myelination and immune response pathways, with a prominent downregulation of alpha-synuclein in Cln1/5 dko mouse brains. The simultaneous loss of both Cln1 and Cln5 genes may enhance the typical pathological phenotypes of these mice by disrupting down shared or convergent pathogenic pathways, which may potentially include interactions of CLN1 and CLN5. Basic characterization of Cln1/5 double knock-out mouse model. Aim was to find possible differentially expressed genes and up-or downregulated pathways in Cln1/5 double knock-out vs. wild-type mouse cortex. Total RNA isolated from 1 month old Cln1-/-/Cln5-/- mouse cortex.
2012-10-31 | E-GEOD-37643 | biostudies-arrayexpress
Project description:PurposeEpileptiform activity limited to deep sources such as the hippocampus currently lacks reliable scalp correlates. Recent studies, however, have found that a subset of hippocampal interictal discharges may be associated with visible scalp signals, suggesting that some types of hippocampal activity may be monitored noninvasively. The purpose of this study is to characterize the relationship between these scalp waveforms and the underlying intracranial activity.MethodsPaired intracranial and scalp EEG recordings obtained from 16 patients were used to identify hippocampal interictal discharges. Discharges were grouped by waveform shape, and spike-triggered averages of the intracranial and scalp signals were calculated for each group. Cross-correlation of intracranial and scalp spike-triggered averages was used to determine their temporal relationship, and topographic maps of the scalp were generated for each group.ResultsCross-correlation of intracranial and scalp correlates resulted in two classes of scalp waveforms-those with and without time delays from the associated hippocampal discharges. Scalp signals with no delay showed topographies with a broad field with higher amplitudes on the side ipsilateral to the discharges and a left-right flip in polarity-observations consistent with the volume conduction of a single unilateral deep source. In contrast, scalp correlates with time lags showed rotational dynamics, suggesting synaptic propagation mechanisms.ConclusionsThe temporal relationship between the intracranial and scalp signals suggests that both volume conduction and synaptic propagation contribute to these scalp manifestations. Furthermore, the topographic evolution of these scalp waveforms may be used to distinguish spikes that are limited to the hippocampus from those that travel to or engage other brain areas.
| S-EPMC8590709 | biostudies-literature
Project description:Recent genome-wide association studies of age-at-onset in Huntington's disease (HD) point to distinct modes of potential disease modification: altering the rate of somatic expansion of the HTT CAG repeat or altering the resulting CAG threshold length-triggered toxicity process. Here, we evaluated the mouse orthologs of two HD age-at-onset modifier genes, FAN1 and RRM2B, for an influence on somatic instability of the expanded CAG repeat in Htt CAG knock-in mice. Fan1 knock-out increased somatic expansion of Htt CAG repeats, in the juvenile- and the adult-onset HD ranges, whereas knock-out of Rrm2b did not greatly alter somatic Htt CAG repeat instability. Simultaneous knock-out of Mlh1, the ortholog of a third HD age-at-onset modifier gene (MLH1), which suppresses somatic expansion of the Htt knock-in CAG repeat, blocked the Fan1 knock-out-induced acceleration of somatic CAG expansion. This genetic interaction indicates that functional MLH1 is required for the CAG repeat destabilizing effect of FAN1 loss. Thus, in HD, it is uncertain whether the RRM2B modifier effect on timing of onset may be due to a DNA instability mechanism. In contrast, the FAN1 modifier effects reveal that functional FAN1 acts to suppress somatic CAG repeat expansion, likely in genetic interaction with other DNA instability modifiers whose combined effects can hasten or delay onset and other CAG repeat length-driven phenotypes.
| S-EPMC7645713 | biostudies-literature
Project description:Neuronal aggregates containing α-synuclein are a pathological hallmark of several degenerative diseases; including Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies. Understanding the process of α-synuclein aggregation, and discovering means of preventing it, may help guide therapeutic strategy and drug design. Recent advances provide tools to induce α-synuclein aggregation in neuronal cultures. Application of exogenous pre-formed fibrillar α-synuclein induces pathological phosphorylation and accumulation of endogenous α-synuclein, typical of that seen in disease. Genomic variability and mutations in α-synuclein and leucine-rich repeat kinase 2 proteins are the major genetic risk factors for Parkinson's disease. Reports demonstrate fibril-induced α-synuclein aggregation is increased in cells from leucine-rich repeat kinase 2 pathogenic mutant (G2019S) overexpressing mice, and variously decreased by leucine-rich repeat kinase 2 inhibitors. Elsewhere in vivo antisense knock-down of leucine-rich repeat kinase 2 protein has been shown to protect mice from fibril-induced α-synuclein aggregation, whereas kinase inhibition did not. To help bring clarity to this issue, we took a purely genetic approach in a standardized neuron-enriched culture, lacking glia. We compared fibril treatment of leucine-rich repeat kinase 2 germ-line knock-out, and G2019S germ-line knock-in, mouse cortical neuron cultures with those from littermates. We found leucine-rich repeat kinase 2 knock-out neurons are resistant to α-synuclein aggregation, which predominantly forms within axons, and may cause axonal fragmentation. Conversely, leucine-rich repeat kinase 2 knock-in neurons are more vulnerable to fibril-induced α-synuclein accumulation. Protection and resistance correlated with basal increases in a lysosome marker in knock-out, and an autophagy marker in knock-in cultures. The data add to a growing number of studies that argue leucine-rich repeat kinase 2 silencing, and potentially kinase inhibition, may be a useful therapeutic strategy against synucleinopathy.
| S-EPMC7273240 | biostudies-literature
Project description:Clinical diagnosis of epilepsy depends heavily on the detection of interictal epileptiform discharges (IEDs) from scalp electroencephalographic (EEG) signals, which by purely visual means is far from straightforward. Here, we introduce a simple signal analysis procedure based on scalp EEG zero-crossing patterns which can extract the spatiotemporal structure of scalp voltage fluctuations. We analyzed simultaneous scalp and intracranial EEG recordings from patients with pharmacoresistant temporal lobe epilepsy. Our data show that a large proportion of intracranial IEDs manifest only as subtle, low-amplitude waveforms below scalp EEG background and could, therefore, not be detected visually. We found that scalp zero-crossing patterns allow detection of these intracranial IEDs on a single-trial level with millisecond temporal precision and including some mesial temporal discharges that do not propagate to the neocortex. Applied to an independent dataset, our method discriminated accurately between patients with epilepsy and normal subjects, confirming its practical applicability.
| S-EPMC7892826 | biostudies-literature
Project description:ObjectiveFunctional connectivity networks (FCNs) based on interictal electroencephalography (EEG) can identify pathological brain networks associated with epilepsy. FCNs are altered by interictal epileptiform discharges (IEDs), but it is unknown whether this is due to the morphology of the IED or the underlying pathological activity. Therefore, we characterized the impact of IEDs on the FCN through simulations and EEG analysis.MethodsWe introduced simulated IEDs to sleep EEG recordings of eight healthy controls and analyzed the effect of IED amplitude and rate on the FCN. We then generated FCNs based on epochs with and without IEDs and compared them to the analogous FCNs from eight subjects with infantile spasms (IS), based on 1340 visually marked IEDs. Differences in network structure and strength were assessed.ResultsIEDs in IS subjects caused increased connectivity strength but no change in network structure. In controls, simulated IEDs with physiological amplitudes and rates did not alter network strength or structure.ConclusionsIncreases in connectivity strength in IS subjects are not artifacts caused by the interictal spike waveform and may be related to the underlying pathophysiology of IS.SignificanceDynamic changes in EEG-based FCNs during IEDs may be valuable for identification of pathological networks associated with epilepsy.
| S-EPMC7784722 | biostudies-literature