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1.
Clin EEG Neurosci ; 54(2): 203-212, 2023 Mar.
Article in English | MEDLINE | ID: mdl-33203220

ABSTRACT

The goal of these studies was to use quantitative (q)EEG techniques on data from children with Angelman syndrome (AS) using spectral power analysis, and to evaluate this as a potential biomarker and quantitative method to evaluate therapeutics. Although characteristic patterns are evident in visual inspection, using qEEG techniques has the potential to provide quantitative evidence of treatment efficacy. We first assessed spectral power from baseline EEG recordings collected from children with AS compared to age-matched neurotypical controls, which corroborated the previously reported finding of increased total power driven by elevated delta power in children with AS. We then retrospectively analyzed data collected during a clinical trial evaluating the safety and tolerability of minocycline (3 mg/kg/d) to compare pretreatment recordings from children with AS (4-12 years of age) to EEG activity at the end of treatment and following washout for EEG spectral power and epileptiform events. At baseline and during minocycline treatment, the AS subjects demonstrated increased delta power; however, following washout from minocycline treatment the AS subjects had significantly reduced EEG spectral power and epileptiform activity. Our findings support the use of qEEG analysis in evaluating AS and suggest that this technique may be useful to evaluate therapeutic efficacy in AS. Normalizing EEG power in AS therefore may become an important metric in screening therapeutics to gauge overall efficacy. As therapeutics transition from preclinical to clinical studies, it is vital to establish outcome measures that can quantitatively evaluate putative treatments for AS and neurological disorders with distinctive EEG patterns.


Subject(s)
Angelman Syndrome , Child , Humans , Angelman Syndrome/diagnosis , Angelman Syndrome/drug therapy , Electroencephalography , Minocycline/therapeutic use , Retrospective Studies , Treatment Outcome
2.
Brain ; 145(4): 1310-1325, 2022 05 24.
Article in English | MEDLINE | ID: mdl-34849602

ABSTRACT

Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient focal malformation of cortical development tissue and in a mouse model of focal malformation of cortical development. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by focal malformation of cortical development in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern and aberrant expression of HCN4 ion channels. Further, 4E-BP1 expression in juvenile focal malformation of cortical development mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat focal malformation of cortical development-related epilepsy during childhood with potentially long-lasting effects in adults.


Subject(s)
Adaptor Proteins, Signal Transducing , Cell Cycle Proteins , Epilepsy , TOR Serine-Threonine Kinases , Adaptor Proteins, Signal Transducing/genetics , Animals , Brain/pathology , Cell Cycle Proteins/genetics , Epilepsy/pathology , Humans , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism , Mice , Neurons/metabolism , Phosphorylation , Seizures/chemically induced , Seizures/genetics , Seizures/metabolism , TOR Serine-Threonine Kinases/metabolism
3.
Mol Autism ; 12(1): 59, 2021 09 15.
Article in English | MEDLINE | ID: mdl-34526125

ABSTRACT

BACKGROUND: Angelman Syndrome (AS) is a rare neurodevelopmental disorder for which there is currently no cure or effective therapeutic. Since the genetic cause of AS is known to be dysfunctional expression of the maternal allele of ubiquitin protein ligase E3A (UBE3A), several genetic animal models of AS have been developed. Both the Ube3a maternal deletion mouse and rat models of AS reliably demonstrate behavioral phenotypes of relevance to AS and therefore offer suitable in vivo systems in which to test potential therapeutics. One promising candidate treatment is insulin-like growth factor-2 (IGF-2), which has recently been shown to ameliorate behavioral deficits in the mouse model of AS and improve cognitive abilities across model systems. METHODS: We used both the Ube3a maternal deletion mouse and rat models of AS to evaluate the ability of IGF-2 to improve electrophysiological and behavioral outcomes. RESULTS: Acute systemic administration of IGF-2 had an effect on electrophysiological activity in the brain and on a metric of motor ability; however the effects were not enduring or extensive. Additional metrics of motor behavior, learning, ambulation, and coordination were unaffected and IGF-2 did not improve social communication, seizure threshold, or cognition. LIMITATIONS: The generalizability of these results to humans is difficult to predict and it remains possible that dosing schemes (i.e., chronic or subchronic dosing), routes, and/or post-treatment intervals other than that used herein may show more efficacy. CONCLUSIONS: Despite a few observed effects of IGF-2, our results taken together indicate that IGF-2 treatment does not profoundly improve behavioral deficits in mouse or rat models of AS. These findings shed cautionary light on the potential utility of acute systemic IGF-2 administration in the treatment of AS.


Subject(s)
Angelman Syndrome , Alleles , Angelman Syndrome/drug therapy , Angelman Syndrome/genetics , Angelman Syndrome/metabolism , Animals , Brain/metabolism , Disease Models, Animal , Insulin-Like Growth Factor II/genetics , Insulin-Like Growth Factor II/metabolism , Insulin-Like Growth Factor II/therapeutic use , Mice , Rats , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
4.
eNeuro ; 8(2)2021.
Article in English | MEDLINE | ID: mdl-33531368

ABSTRACT

Angelman syndrome (AS) is a neurodevelopmental disorder with unique behavioral phenotypes, seizures, and distinctive electroencephalographic (EEG) patterns. Recent studies identified motor, social communication, and learning and memory deficits in a CRISPR engineered rat model with a complete maternal deletion of the Ube3a gene. It is unknown whether this model recapitulates other aspects of the clinical disorder. We report here the effect of Ube3a maternal deletion in the rat on epileptiform activity, seizure threshold, and quantitative EEG. Using video-synchronized EEG (vEEG) monitoring, we assessed spectral power and epileptiform activity early postnatally through adulthood. While EEG power was similar to wild-type (WT) at 1.5 weeks postnatally, at all other ages analyzed, our findings were similar to the AS phenotype in mice and humans with significantly increased δ power. Analysis of epileptiform activity in juvenile and adult rats showed increased time spent in epileptiform activity in AS compared with WT rats. We evaluated seizure threshold using pentylenetetrazol (PTZ), audiogenic stimulus, and hyperthermia to provoke febrile seizures (FSs). Behavioral seizure scoring following PTZ induction revealed no difference in seizure threshold in AS rats, however behavioral recovery from the PTZ-induced seizure was longer in the adult group with significantly increased hippocampal epileptiform activity during this phase. When exposed to hyperthermia, AS rat pups showed a significantly lower temperature threshold to first seizure than WT. Our findings highlight an age-dependence for the EEG and epileptiform phenotypes in a preclinical model of AS, and support the use of quantitative EEG and increased δ power as a potential biomarker of AS.


Subject(s)
Angelman Syndrome , Angelman Syndrome/genetics , Animals , Electroencephalography , Gene Deletion , Mice , Phenotype , Rats , Seizures/genetics , Ubiquitin-Protein Ligases/genetics
5.
Sci Rep ; 10(1): 4043, 2020 03 04.
Article in English | MEDLINE | ID: mdl-32132552

ABSTRACT

Status epilepticus (SE) is a prevalent disorder associated with significant morbidity, including the development of epilepsy and mortality. Cardiac arrhythmias (i.e. inappropriate sinus tachycardia and bradycardia, asystole, and atrioventricular blocks) are observed in patients following SE. We characterized ictal (during a seizure) and interictal (between seizure) cardiac arrhythmogenesis following SE using continuous electrocardiography and video electroencephalography (vEEG) recordings throughout a 14-day monitoring period in an intrahippocampal chemoconvulsant mouse model that develops epilepsy. We quantified heart rhythm abnormalities and examined whether the frequency of cardiac events correlated with epileptiform activity, circadian (light/dark) cycle, the presence of seizures, and survival during this period of early epileptogenesis (the development of epilepsy) following SE. Shortly following SE, mice developed an increased interictal heart rate and heart rhythm abnormalities (i.e. sinus pause and sinus arrhythmias) when compared to control mice. Heart rhythm abnormalities were more frequent during the light cycle and were not correlated with increased epileptiform activity or seizure frequency. Finally, SE animals had early mortality, and a death event captured during vEEG recording demonstrated severe bradycardia prior to death. These cardiac changes occurred within 14 days after SE and may represent an early risk factor for sudden death following SE.


Subject(s)
Arrhythmias, Cardiac , Circadian Rhythm/drug effects , Electroencephalography , Kainic Acid/adverse effects , Status Epilepticus , Animals , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/pathology , Arrhythmias, Cardiac/physiopathology , Disease Models, Animal , Kainic Acid/pharmacology , Male , Mice , Status Epilepticus/chemically induced , Status Epilepticus/physiopathology
6.
Sci Rep ; 7(1): 8451, 2017 08 16.
Article in English | MEDLINE | ID: mdl-28814801

ABSTRACT

Angelman syndrome (AS) is a genetic neurodevelopmental disorder, most commonly caused by deletion or mutation of the maternal allele of the UBE3A gene, with behavioral phenotypes and seizures as key features. Currently no treatment is available, and therapeutics are often ineffective in controlling AS-associated seizures. Previous publications using the Ube3a maternal deletion model have shown behavioral and seizure susceptibility phenotypes, however findings have been variable and merit characterization of electroencephalographic (EEG) activity. In this study, we extend previous studies comparing the effect of genetic background on the AS phenotype by investigating the behavioral profile, EEG activity, and seizure threshold. AS C57BL/6J mice displayed robust behavioral impairments, spontaneous EEG polyspikes, and increased cortical and hippocampal power primarily driven by delta and theta frequencies. AS 129 mice performed poorly on wire hang and contextual fear conditioning and exhibited a lower seizure threshold and altered spectral power. AS F1 hybrid mice (C57BL/6J × 129) showed milder behavioral impairments, infrequent EEG polyspikes, and fewer spectral power alterations. These findings indicate the effect of common genetic backgrounds on the Ube3a maternal deletion behavioral, EEG, and seizure threshold phenotypes. Our results will inform future studies on the optimal strain for evaluating therapeutics with different AS-like phenotypes.


Subject(s)
Angelman Syndrome/metabolism , Disease Models, Animal , Seizures/metabolism , Ubiquitin-Protein Ligases/deficiency , Angelman Syndrome/genetics , Angelman Syndrome/physiopathology , Animals , Electroencephalography , Fear/physiology , Female , Male , Maze Learning/physiology , Memory/physiology , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/physiology , Phenotype , Seizures/genetics , Seizures/physiopathology , Species Specificity , Ubiquitin-Protein Ligases/genetics
7.
eNeuro ; 4(3)2017.
Article in English | MEDLINE | ID: mdl-28612047

ABSTRACT

Numerous studies have shown epilepsy-associated cognitive deficits, but less is known about the effects of one single generalized seizure. Recent studies demonstrate that a single, self-limited seizure can result in memory deficits and induces hyperactive phosphoinositide 3-kinase/Akt (protein kinase B)/mechanistic target of rapamycin (PI3K/Akt/mTOR) signaling. However, the effect of a single seizure on subcellular structures such as dendritic spines and the role of aberrant PI3K/Akt/mTOR signaling in these seizure-induced changes are unclear. Using the pentylenetetrazole (PTZ) model, we induced a single generalized seizure in rats and: (1) further characterized short- and long-term hippocampal and amygdala-dependent memory deficits, (2) evaluated whether there are changes in dendritic spines, and (3) determined whether inhibiting hyperactive PI3K/Akt/mTOR signaling rescued these alterations. Using the PI3K inhibitor wortmannin (Wort), we partially rescued short- and long-term memory deficits and altered spine morphology. These studies provide evidence that pathological PI3K/Akt/mTOR signaling plays a role in seizure-induced memory deficits as well as aberrant spine morphology.


Subject(s)
Androstadienes/therapeutic use , Dendritic Spines/drug effects , Memory Disorders/drug therapy , Memory Disorders/etiology , Protein Kinase Inhibitors/therapeutic use , Seizures/complications , Signal Transduction/drug effects , Animals , Animals, Newborn , Convulsants/toxicity , Dendritic Spines/ultrastructure , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Fear , Female , Male , Pentylenetetrazole/toxicity , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Seizures/chemically induced , Seizures/pathology , Signal Transduction/physiology , Wortmannin
8.
J Neurosci ; 34(11): 3826-40, 2014 Mar 12.
Article in English | MEDLINE | ID: mdl-24623762

ABSTRACT

Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid ß (Aß) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of Aß with a γ-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not Aß overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology.


Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/physiopathology , Amyloid beta-Protein Precursor/genetics , Cerebral Cortex/physiopathology , Electroencephalography , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Animals , Disease Models, Animal , Entropy , Female , Gene Knock-In Techniques , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Neurological , Neural Inhibition/physiology , Presenilin-1/genetics , Seizures/chemically induced , Seizures/physiopathology , Suppression, Genetic , Transgenes/physiology
9.
J Neurosci ; 32(31): 10574-86, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22855807

ABSTRACT

The tet-off system has been widely used to create transgenic models of neurological disorders including Alzheimer's, Parkinson's, Huntington's, and prion disease. The utility of this system lies in the assumption that the tetracycline transactivator (TTA) acts as an inert control element and does not contribute to phenotypes under study. Here we report that neuronal expression of TTA can affect hippocampal cytoarchitecture and behavior in a strain-dependent manner. While studying neurodegeneration in two tet-off Alzheimer's disease models, we unexpectedly discovered neuronal loss within the dentate gyrus of single transgenic TTA controls. Granule neurons appeared most sensitive to TTA exposure during postnatal development, and doxycycline treatment during this period was neuroprotective. TTA-induced degeneration could be rescued by moving the transgene onto a congenic C57BL/6J background and recurred on reintroduction of either CBA or C3H/He backgrounds. Quantitative trait analysis of B6C3 F2 TTA mice identified a region on Chromosome 14 that contains a major modifier of the neurodegenerative phenotype. Although B6 mice were resistant to degeneration, they were not ideal for cognitive testing. F1 offspring of TTA C57BL/6J and 129X1/SvJ, FVB/NJ, or DBA/1J showed improved spatial learning, but TTA expression caused subtle differences in contextual fear conditioning on two of these backgrounds, indicating that strain and genotype can interact independently under different behavioral settings. All model systems have limitations that should be recognized and mitigated where possible; our findings stress the importance of mapping the effects caused by TTA alone when working with tet-off models.


Subject(s)
Mental Disorders/genetics , Mental Disorders/metabolism , Neurotoxicity Syndromes/genetics , Neurotoxicity Syndromes/metabolism , Tetracycline/metabolism , Trans-Activators/genetics , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Analysis of Variance , Animals , Anti-Bacterial Agents/pharmacology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Chromosome Mapping , Conditioning, Psychological/physiology , Dentate Gyrus/metabolism , Dentate Gyrus/pathology , Disease Models, Animal , Doxycycline/pharmacology , Exploratory Behavior/physiology , Fear/physiology , Female , Male , Maze Learning/physiology , Mental Disorders/pathology , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Transgenic , Mutation/genetics , Neurotoxicity Syndromes/pathology , Species Specificity , tau Proteins/genetics
10.
Mol Neurodegener ; 7: 28, 2012 Jun 18.
Article in English | MEDLINE | ID: mdl-22709352

ABSTRACT

BACKGROUND: Transgenic mice expressing disease-associated proteins have become standard tools for studying human neurological disorders. Transgenes are often expressed using promoters chosen to drive continuous high-level expression throughout life rather than temporal and spatial fidelity to the endogenous gene. This approach has allowed us to recapitulate diseases of aging within the two-year lifespan of the laboratory mouse, but has the potential for creating aberrant phenotypes by mechanisms unrelated to the human disorder. RESULTS: We show that overexpression of the Alzheimer's-related amyloid precursor protein (APP) during early postnatal development leads to severe locomotor hyperactivity that can be significantly attenuated by delaying transgene onset until adulthood. Our data suggest that exposure to transgenic APP during maturation influences the development of neuronal circuits controlling motor activity. Both when matched for total duration of APP overexpression and when matched for cortical amyloid burden, animals exposed to transgenic APP as juveniles are more active in locomotor assays than animals in which APP overexpression was delayed until adulthood. In contrast to motor activity, the age of APP onset had no effect on thigmotaxis in the open field as a rough measure of anxiety, suggesting that the interaction between APP overexpression and brain development is not unilateral. CONCLUSIONS: Our findings indicate that locomotor hyperactivity displayed by the tet-off APP transgenic mice and several other transgenic models of Alzheimer's disease may result from overexpression of mutant APP during postnatal brain development. Our results serve as a reminder of the potential for unexpected interactions between foreign transgenes and brain development to cause long-lasting effects on neuronal function in the adult. The tet-off APP model provides an easy means of avoiding developmental confounds by allowing transgene expression to be delayed until the mice reach adulthood.


Subject(s)
Amyloid beta-Protein Precursor/genetics , Locomotion/genetics , Aging , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Animals, Genetically Modified , Brain/metabolism , Disease Models, Animal , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/metabolism , Transgenes
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