A Genetic Switch for Epilepsy in Adult Mice

Krestel, Heinz; Shimshek, Derya R.; Jensen, Vidar R.; Nevian, Thomas; Kim, Jin−Hyun; Geng, Yu; Bast, Thomas; Depaulis, Antoine; Shi, Kai; Schwenk, Frieder; Bujard, Hermann; Hvalby, Øivind; Sprengel, Rolf; Seeburg, Peter H.

doi:10.1523/jneurosci.4579-03.2004

Cited by 73 publications

(105 citation statements)

References 39 publications

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“…Litters were fostered to Dox-naïve dams (Fig. 1C), thus activating tTA, which was transgenically expressed in principal neurons of the forebrain via the α-calcium/calmodulin-dependent protein kinase II (α−CamKII) promoter (16)(17)(18). In absence of Dox, tTA induced Cre expression and, subsequently, Npy1r gene inactivation in juvenile Npy1r 2lox /Tg αCamKII-tTA/LC1 mice (Npy1r rfb mice; rfb, reduced forebrain expression).…”

Section: Resultsmentioning

confidence: 99%

“…In absence of Dox, tTA induced Cre expression and, subsequently, Npy1r gene inactivation in juvenile Npy1r 2lox /Tg αCamKII-tTA/LC1 mice (Npy1r rfb mice; rfb, reduced forebrain expression). Cre-mediated recombination of floxed cellular target alleles in excitatory neurons of the forebrain is complete between postnatal days (P)35 and 50 (17,19).…”

Section: Resultsmentioning

confidence: 99%

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Regulatory functions of limbic Y1 receptors in body weight and anxiety uncovered by conditional knockout and maternal care

Bertocchi

Oberto

Longo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Neuropeptide Y (NPY) plays an important role in stress, anxiety, obesity, and energy homeostasis via activation of NPY-Y1 receptors (Y1Rs) in the brain. However, global knockout of the Npy1r gene has low or no impact on anxiety and body weight. To uncover the role of limbic Y1Rs, we generated conditional knockout mice in which the inactivation of the Npy1r gene was restricted to excitatory neurons of the forebrain, starting from juvenile stages (Npy1r rfb ). Npy1r rfb mice exhibited increased anxiety and reduced body weight, less adipose tissue, and lower serum leptin levels. Npy1r rfb mutants also had a hyperactive hypothalamic-pituitaryadrenocortical axis, as indicated by higher peripheral corticosterone and higher density of NPY immunoreactive fibers and corticotropin releasing hormone immunoreactive cell bodies in the paraventricular hypothalamic nucleus. Importantly, through fostering experiments, we determined that differences in phenotype between Npy1r rfb and Npy1r 2lox mice became apparent when both genotypes were raised by FVB/J but not by C57BL/6J dams, suggesting that limbic Y1Rs are key targets of maternal care-induced programming of anxiety and energy homeostasis. where it is involved in the regulation of anxiety, stress reactions, energy balance, circadian rhythms, and cognition (1-3). Clinical studies suggest that NPY plays an important role in the response to stress and in psychiatric disorders (4). In humans, NPY haploinsufficiency is correlated with characteristic brain responses to emotional and stress challenges and with trait anxiety (5). Intracerebroventricular injection of NPY reduces both anxiety-and stress-related behavior in several animal models, an effect that is primarily mediated by Y1 receptors (Y1Rs) expressed in amygdala, hippocampus, and locus coeruleus (6-9). The implications of a role of endogenous NPY in acting via Y1R to control emotionality, mood, and stress reactions have been probed with Y1R-selective antagonists and antisense oligonucleotides (1). NPY exerts its anxiolytic-like effect in the brain via interactions with the hypothalamic-pituitaryadrenocortical (HPA) axis and corticosteroids. Indeed, a functional antagonism between NPY and corticotropin releasing hormone (CRH) has been demonstrated in various CNS nuclei along the stress/anxiety circuits (10).In addition to its crucial role in emotional behavior, NPY potently stimulates feeding, reduces energy expenditure, and induces obesity via the activation of Y1R expressed in the hypothalamus (1). However, global Npy1r gene knockout mice showed only minor deficiencies in energy homeostasis, feeding, and anxiety (11)(12)(13)(14).To study the function of Y1R expressed in the limbic system and to exclude effects induced by the Npy1r gene inactivation in early development, we restricted the ablation of Y1R to excitatory neurons in the postnatal forebrain of mice by using the Cre-loxP system (Fig. 1A). In addition, because early postnatal environment can modulate NPY levels (15), gene-targeted pups were reared by two diffe...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Regulatory functions of limbic Y1 receptors in body weight and anxiety uncovered by conditional knockout and maternal care

Bertocchi

Oberto

Longo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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“…The surgical procedure used was adapted from previous studies using similar equipment. 46,47 Telemetric EEG recording was performed after surgical implantation of telemetric transmitters (TA10EA-F20; DSI). Briefly, the skin overlaying skull and neck was incised, and a subcutaneous skin pouch was created by blunt dissection underneath the skin on the back of the animal.…”

Section: Discussionmentioning

confidence: 99%

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

et al. 2014

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Kainic acid (KA)-induced seizures followed by neuronal death are associated with neuroinflammation and blood-brain barrier (BBB) leakage. Tonicity-responsive enhancer binding protein (TonEBP) is known as a transcriptional factor activating osmoprotective genes, and in brain, it is expressed in neuronal nuclei. Thus dysregulation of TonEBP may be involved in the pathology of KA-induced seizures. Here we used TonEBP heterozygote ( þ / À ) mice to study the roles of TonEBP. Electroencephalographic study showed that TonEBP ( þ / À ) mice reduced seizure frequency and severity compared with wild type during KA-induced status epilepticus. Immunohistochemistry and western blotting analysis showed that KA-induced neuroinflammation and BBB leakage were dramatically reduced in TonEBP ( þ / À ) mice. Similarly, TonEBP-specific siRNA reduced glutamate-induced death in HT22 hippocampal neuronal cells. TonEBP haplodeficiency prevented KA-induced nuclear translocation of NF-jB p65 and attenuated inflammation. Our findings identify TonEBP as a critical regulator of neuroinflammation and BBB leakage in KA-induced seizures, which suggests TonEBP as a good therapeutic target.

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“…Several up-reg- ulated genes are involved in neuroprotection (Cdk6, Col8a1, Dnajb6, Hdac9, and Id3) and repair processes in astrocytes (Itsn, Rgs3, and Clint1), whereas others are associated with synaptic trafficking, which might be of interest in correlation with the important role of glutamate receptor channels in synaptic plasticity (37). For example, Dlgap2, a member of the scaffolding protein family SAPAP, is involved in activity-mediated modification of postsynaptic densities (38).…”

Section: Discussionmentioning

confidence: 99%

Requirement of the RNA-editing Enzyme ADAR2 for Normal Physiology in Mice

Horsch

Seeburg

Adler

et al. 2011

Journal of Biological Chemistry

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ADAR2, an RNA editing enzyme that converts specific adenosines to inosines in certain pre-mRNAs, often leading to amino acid substitutions in the encoded proteins, is mainly expressed in brain. Of all ADAR2-mediated edits, a single one in the pre-mRNA of the AMPA receptor subunit GluA2 is essential for survival. Hence, early postnatal death of mice lacking ADAR2 is averted when the critical edit is engineered into both GluA2 encoding Gria2 alleles. Adar2 ؊/؊ /Gria2 R/R mice display normal appearance and life span, but the general phenotypic effects of global lack of ADAR2 have remained unexplored. Here we have employed the Adar2 ؊/؊ /Gria2 R/R mouse line, and Gria2 R/R mice as controls, to study the phenotypic consequences of loss of all ADAR2-mediated edits except the critical one in GluA2. Our extended phenotypic analysis covering ϳ320 parameters identified significant changes related to absence of ADAR2 in behavior, hearing ability, allergy parameters and transcript profiles of brain.The most common RNA modification in higher organisms is the enzymatic deamination of specific adenosines to inosine (A-to-I editing), wrought by members of the ADAR protein family (1). ADARs, short for adenosine deaminases acting on RNA, were discovered by their ability to convert in vitro in double-stranded RNA ϳ50% of the adenosines to inosines, thus destabilizing the double-stranded structure (2). Occurring in worms, flies and mammals, these enigmatic enzymes are now known to switch specific adenosines to inosine in mostly primary nuclear transcripts (3-6). A-to-I editing often recodes amino acids within the gene-encoded protein, based on reading inosine as guanosine by the translational machinery, and can remove or create splice acceptor sites (7), thus altering the pattern of RNA splicing. Moreover, editing in 5Ј and 3ЈUTRs and intronic sequence may lead to altered translational efficiency,

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A Genetic Switch for Epilepsy in Adult Mice

Cited by 73 publications

References 39 publications

Regulatory functions of limbic Y1 receptors in body weight and anxiety uncovered by conditional knockout and maternal care

Regulatory functions of limbic Y1 receptors in body weight and anxiety uncovered by conditional knockout and maternal care

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

Requirement of the RNA-editing Enzyme ADAR2 for Normal Physiology in Mice

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