Spontaneous epileptiform discharges in a mouse model of Alzheimer's disease are suppressed by antiepileptic drugs that block sodium channels

Ziyatdinova, Sofya; Gurevicius, Kestutis; Kutchiashvili, Nino; Bolkvadze, Tamuna; Nissinen, Jari; Tanila, Heikki; Pitkänen, Asla

doi:10.1016/j.eplepsyres.2011.01.003

Cited by 95 publications

(92 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Alzheimer's disease (Tg2576) and Down syndrome (Ts65Dn) mice, which overexpress human and mouse APP respectively, are highly susceptible to AGS (Westmark et al, 2010). Numerous mouse models that express altered APP or metabolite levels exhibit elevated rates of spontaneous or provoked seizures (Moechars et al, 1996; Steinbach et al, 1998; Del Vecchio et al, 2004; Lalonde et al, 2005; Palop et al, 2007; Kobayashi et al, 2008; Westmark et al, 2008; Minkeviciene et al, 2009; Ziyatdinova et al, 2011; Sanchez et al, 2012) while suppression of transgenic APP in Alzheimer's disease mice during postnatal development delays the onset of EEG abnormalities (Born et al, 2014). …”

Section: Genetic Reduction Of App Rescues Hyperexcitability In Fmr1komentioning

confidence: 99%

APP Causes Hyperexcitability in Fragile X Mice

Westmark

Chuang

Hays

et al. 2016

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Amyloid-beta protein precursor (APP) and metabolite levels are altered in fragile X syndrome (FXS) patients and in the mouse model of the disorder, Fmr1KO mice. Normalization of APP levels in Fmr1KO mice (Fmr1KO/APPHET mice) rescues many disease phenotypes. Thus, APP is a potential biomarker as well as therapeutic target for FXS. Hyperexcitability is a key phenotype of FXS. Herein, we determine the effects of APP levels on hyperexcitability in Fmr1KO brain slices. Fmr1KO/APPHET slices exhibit complete rescue of UP states in a neocortical hyperexcitability model and reduced duration of ictal discharges in a CA3 hippocampal model. These data demonstrate that APP plays a pivotal role in maintaining an appropriate balance of excitation and inhibition (E/I) in neural circuits. A model is proposed whereby APP acts as a rheostat in a molecular circuit that modulates hyperexcitability through mGluR5 and FMRP. Both over- and under-expression of APP in the context of the Fmr1KO increases seizure propensity suggesting that an APP rheostat maintains appropriate E/I levels but is overloaded by mGluR5-mediated excitation in the absence of FMRP. These findings are discussed in relation to novel treatment approaches to restore APP homeostasis in FXS.

show abstract

Section: Genetic Reduction Of App Rescues Hyperexcitability In Fmr1komentioning

confidence: 99%

APP Causes Hyperexcitability in Fragile X Mice

Westmark

Chuang

Hays

et al. 2016

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Seizure phenotype (spikes and sharp waves) is most often noticed in models carrying the Swedish mutation, including Tg2576, APP23, hAPPJ20, APdE9 [91,92], and apolipoprotein E4 [94], which strongly contribute to impaired functional connectivity across brain regions. Antiepileptic drugs that block sodium channels suppressed neural hyperactivation and epileptiform discharges in APdE9 [95]. The antiepileptic drug levetiracetam effectively suppressed abnormal spiking activity in hAPP mice and reversed their behavioral abnormalities and cognitive impairments [96], whereas cessation of levetiracetam treatment was accompanied by the reappearance of the recurrent aberrant network activity, dysfunctional epileptiform network, and behavioral abnormalities [96].…”

Section: P-eeg In Modeled Animalsmentioning

confidence: 99%

Pharmaco-EEG Studies in Animals: An Overview of Contemporary Translational Applications

Drinkenburg

Ruigt²,

Ahnaou

2015

Neuropsychobiology

View full text Add to dashboard Cite

The contemporary value of animal pharmaco-electroencephalography (p-EEG)-based applications are strongly interlinked with progress in recording and neuroscience analysis methodology. While p-EEG in humans and animals has been shown to be closely related in terms of underlying neuronal substrates, both translational and back-translational approaches are being used to address extrapolation issues and optimize the translational validity of preclinical animal p-EEG paradigms and data. Present applications build further on animal p-EEG and pharmaco-sleep EEG findings, but also on stimulation protocols, more specifically pharmaco-event-related potentials. Pharmaceutical research into novel treatments for neurological and psychiatric diseases has employed an increasing number of pharmacological as well as transgenic models to assess the potential therapeutic involvement of different neurochemical systems and novel drug targets as well as underlying neuronal connectivity and synaptic function. Consequently, p-EEG studies, now also readily applied in modeled animals, continue to have an important role in drug discovery and development, with progressively more emphasis on its potential as a central readout for target engagement and as a (translational) functional marker of neuronal circuit processes underlying normal and pathological brain functioning. In a similar vein as was done for human p-EEG studies, the contribution of animal p-EEG studies can further benefit by adherence to guidelines for methodological standardization, which are presently under construction by the International Pharmaco-EEG Society (IPEG).

show abstract

“…Adult rats that were prenatally exposed to VPA were found to have behavioral impairments such as decreased rearing and hole-poking along with increased locomotor activity in novel environments (Sandhya et al 2012). VPA reduce slow threshold (T type) calcium channel current and voltage-gated Na + channel activity while γ-aminobutyric acid (GABA) synthesis in the substantia nigra is increased (Kelly et al 1990;Löscher 1999;Ziyatdinova et al 2011). Furthermore, VPA has antiexcitotoxic effects on N-methyl-D-aspartate-induced transient depolarization (Zeise et al 1991) and decreases glutamate-mediated excitotoxic damage in a porcine model of traumatic brain injury (Hwabejire et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Valproic acid decreases cell proliferation and migration in the cerebellum of zebrafish larvae

Lee

2014

Animal Cells and Systems

View full text Add to dashboard Cite

Valproic acid (VPA) is used as an antiepileptic drug or mood stabilizer. Recent studies have shown that exposure to VPA during embryonic development alters neural progenitor cell proliferation. The main goal of this investigation was to elucidate the effects of VPA on cell proliferation in the cerebellum of zebrafish larvae using immunohistochemistry. 5-bromo-2'-deoxyuridine (BrdU) and proliferating cell nuclear antigen (PCNA)-labeled cells were mostly found in the ventral cerebellum proliferation zone and external granular layer of the cerebellum from 5 days postfertilization zebrafish immediately after treatment with BrdU for 12 h. Subsequently, BrdU-labeled cells were mostly found in the medial zone of the cerebellar plate 48 h after terminating BrdU treatment. Pretreatment with 2-mM VPA for 3 h prior to BrdU exposure reduced the number of BrdU-labeled cells both immediately and 48 h after terminating BrdU exposure. Posttreatment with VPA following BrdU exposure reduced the migration of BrdU-labeled cells, represented by a decreased number of BrdUpositive cells in the medial zone of the cerebellar plate. These results suggest that VPA may delay brain development by hindering cell proliferation and migration during the early developmental period.

show abstract

Spontaneous epileptiform discharges in a mouse model of Alzheimer's disease are suppressed by antiepileptic drugs that block sodium channels

Cited by 95 publications

References 42 publications

APP Causes Hyperexcitability in Fragile X Mice

APP Causes Hyperexcitability in Fragile X Mice

Pharmaco-EEG Studies in Animals: An Overview of Contemporary Translational Applications

Valproic acid decreases cell proliferation and migration in the cerebellum of zebrafish larvae

Contact Info

Product

Resources

About