Reduced startle reactivity and plasticity in transgenic mice overexpressing corticotropin-releasing hormone

Dirks, Anneloes; Groenink, Lucianne; Schipholt, Marlies Iutje; Gugten, Jan van der; Hijzen, Theo H.; Geyer, Mark A.; Olivier, Berend

doi:10.1016/s0006-3223(01)01323-3

Cited by 75 publications

(57 citation statements)

References 40 publications

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“…These data are consistent with our and others' previous reports showing reduced PPI and habituation following developmental or lifetime CRHOE (Dirks et al, 2002;Groenink et al, 2008;Toth et al, 2014). Pharmacological and genetic manipulation studies reported increased startle and reduced PPI following CRHR1 receptor hypersignaling, whereas CRHR2 receptor stimulation increased PPI (Risbrough et al, 2003(Risbrough et al, , 2004.…”

Section: Discussionsupporting

confidence: 93%

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Tóth

Flandreau

Deslauriers

et al. 2015

Neuropsychopharmacol

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Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH overexpression during early-life (pre-puberty, CRHOE dev ) in double-mutant mice (Camk2a-rtta2 × tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood. In one cohort of CRHOE dev exposed and unexposed mice, avoidance and arousal behaviors were examined 7-15 days after exposure to predator stress. In another cohort, gene expression changes in Crhr1, Crhr2, and Fkbp51 in forebrain of CRHOE dev exposed and unexposed mice were examined 7 days after predator stress. CRHOE dev induced robust increases in startle reactivity and reductions in startle inhibition independently of predator stress in both male and female mice. Avoidance behaviors after predator stress were highly dependent on sex and CRHOE dev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOE dev , males developed significant avoidance only when exposed to both CRHOE dev and stress. Quantitative real-time-PCR analysis indicated that CRHOE dev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress, whereas males exposed to CRHOE dev did not. Similar to CRHOE dev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and CRHOE dev exposure in males, but not in females. These findings indicate that forebrain CRH hyper-signaling in early-life is sufficient to increase enduring effects of adult trauma and attenuate Crhr2 expression changes in response to stress in males. These data support growing evidence for significant sex differences in response to trauma, and support further study of CRHR2 as a candidate mechanism for PTSD risk.

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Section: Discussionsupporting

confidence: 93%

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Tóth

Flandreau

Deslauriers

et al. 2015

Neuropsychopharmacol

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“…Our mice are different compared to Stenzel-Poore group's CRH-Tg mice (Stenzel-Poore et al, 1992), which showed Cushingoid features: truncal obesity with large adipose deposits, muscle wasting, bilateral symmetric hair loss, and abnormally transparent skin. Our CRH overexpressing mice showed decreased body weight compared to control mice comparable to the second published CRH-Tg mouse line (Dirks et al, 2002b). However, the latter also showed…”

Section: Crh Overexpression Decreased Body Weighsupporting

confidence: 76%

“…The first described CRH overexpressing mouse line (Stenzel-Poore et al, 1992) displayed truncal obesity compared to control mice because of the increased corticosterone resembling a Cushing syndrome-like phenotype. However, the second CRH overexpressing mouse line generated revealed significantly lower body weights than control mice (Dirks et al, 2002b). To assess the body weight of our CRH overexpressing mice, we weighted 4-month old mice.…”

Section: Body Weightmentioning

confidence: 99%

Site-specific overexpression of corticotropin-releasing hormone (CRH) in the mouse brain – modelling central CRH system hyperactivity

Steiner²,

Engelholm³

et al. 2005

Pharmacopsychiatry

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“…The relationship between CRH and schizophrenia has been demonstrated also in experimental animals. Chronically increased CRH level in transgenic mice overexpressing CRH is associated with sensorimotor gating deficits (prepulse-induced inhibition of acoustic startle response), which is a behavioral disturbance typical of schizophrenia (Dirks et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Also, in the transgenic mice overexpressing CRH, some antipsychotic drugs alleviated sensorimotor gating deficits (Dirks et al, 2002). However, there are only few data concerning the intracellular mechanism of modulatory effects of antipsychotics on HPA axis activity and the density or function of GR.…”

Section: Introductionmentioning

confidence: 99%

Antipsychotic Drugs Inhibit the Human Corticotropin-Releasing-Hormone Gene Promoter Activity in Neuro-2A Cells—an Involvement of Protein Kinases

Basta‐Kaim

Budziszewska

Jaworska-Feil

et al. 2005

Neuropsychopharmacol

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Antipsychotic drugs can regulate transcription of some genes, including those involved in regulation of hypothalamic-pituitary-adrenal (HPA) axis, whose activity is frequently disturbed in schizophrenic patients. However, molecular mechanism of antipsychotic drug action on the corticotropin-releasing hormone (CRH) gene activity has not been investigated so far. This study was undertaken to examine the influence of conventional and atypical antipsychotic drugs on the CRH gene promoter activity in differentiated Neuro-2A cell cultures stably transfected with a human CRH promoter fragment linked to the chloramphenicol acetyltransferase (CAT) reporter gene. It has been found that chlorpromazine (0.1-5.0 mM), haloperidol (0.5-5.0 mM), clozapine (1.0-5.0 mM), thioridazine (1.0-5.0 mM), promazine (5.0 and 10 mM), risperidone (5.0 and 10.0 mM), and raclopride (only at the highest used concentrations, ie 30 and 100 mM) present in culture medium for 5 days inhibited the CRH-CAT activity. Sulpiride and remoxipride had no effect. Since CRH gene activity is most potently enhanced by cAMP/protein kinase A pathway, the effect of antipsychotics on the forskolin-induced CRH-CAT activity was determined. Chlorpromazine (1.0-5.0 mM), haloperidol (1.0-5.0 mM), clozapine (1.0-5.0 mM), thioridazine (3.0 and 5.0 mM), and raclopride (30 and 100 mM), but not promazine, sulpiride, risperidone, and remoxipride, inhibited the forskolin-stimulated CRH gene promoter activity. A possible involvement of protein kinases in chlorpromazine and clozapine inhibitory action on CRH activity was also investigated. It was found that wortmannin (0.01 and 0.02 mM), an inhibitor of phosphatidylinositol 3-kinase (PI3-K), significantly attenuated the inhibitory effect of chlorpromazine and clozapine on CRH gene promoter activity. In line with these results, a Western blot study showed that these drugs increased phospho-Ser-473 Akt level, had no effect on total Akt, and decreased glycogen synthase kinase-3b level. Additionally, we found that clozapine decreased protein kinase C (PKC) level and that its action on CRH activity was attenuated by PKC activator (TPA, 0.1 mM). The obtained results indicate that inhibition of CRH gene promoter activity by some antipsychotic drugs may be a molecular mechanism responsible for their inhibitory action on HPA axis activity. Clozapine and chlorpromazine action on CRH activity operates mainly through activation of the PI3-K/Akt pathway. Moreover, PKC-mediated pathway seems to be involved in clozapine action on CRH gene activity.

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Reduced startle reactivity and plasticity in transgenic mice overexpressing corticotropin-releasing hormone

Cited by 75 publications

References 40 publications

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Site-specific overexpression of corticotropin-releasing hormone (CRH) in the mouse brain – modelling central CRH system hyperactivity

Antipsychotic Drugs Inhibit the Human Corticotropin-Releasing-Hormone Gene Promoter Activity in Neuro-2A Cells—an Involvement of Protein Kinases

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