Atlas of transgenic Tet-Off Ca2+/calmodulin-dependent protein kinase II and prion protein promoter activity in the mouse brain

Odeh, Francis; Leergaard, Trygve B.; Boy, Jana; Schmidt, Thorsten; Rieß, Olaf; Bjaalie, Jan G.

doi:10.1016/j.neuroimage.2010.11.032

Cited by 21 publications

(33 citation statements)

References 49 publications

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“…Thereafter, mice were either further kept on doxycycline or without doxycycline for 4 weeks to allow transgene expression. The characterization of the spatial distribution of the transgene expression, using immunohistochemical staining against the reporter gene, revealed that the mCherry expression has a labeling pattern typical for CaMKII promoter activity, primary distributed to forebrain neurons, similar to the previous reports (Mayford et al, 1996; Odeh et al, 2011) (Figure 1B). The evaluation of the doxycycline-regulated transgene expression demonstrated that doxycycline treatment completely suppressed the mCherry immunofluorescence labeling (Figure S3A) and mRNA and protein expression in the brain to undetectable levels (Figures 1D and S3B).…”

Section: Resultssupporting

confidence: 84%

Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a

Serchov

Clement

Schwarz

et al. 2015

Neuron

170

199

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SUMMARY Major depressive disorder is among the most commonly diagnosed disabling mental diseases. Several non-pharmacological treatments of depression upregulate adenosine concentration and/or adenosine A1 receptors (A1R) in the brain. To test whether enhanced A1R signaling mediates antidepressant effects, we generated a transgenic mouse with enhanced doxycycline-regulated A1R expression, specifically in forebrain neurons. Upregulating A1R led to pronounced acute and chronic resilience toward depressive-like behavior in various tests. Conversely, A1R knockout mice displayed an increased depressive-like behavior and were resistant to the antidepressant effects of sleep deprivation (SD). Various antidepressant treatments increase homer1a expression in medial prefrontal cortex (mPFC). Specific siRNA knockdown of homer1a in mPFC enhanced depressive-like behavior and prevented the antidepressant effects of A1R upregulation, SD, imipramine, and ketamine treatment. In contrast, viral overexpression of homer1a in the mPFC had antidepressant effects. Thus, increased expression of homer1a is a final common pathway mediating the antidepressant effects of different antidepressant treatments.

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Section: Resultssupporting

confidence: 84%

Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a

Serchov

Clement

Schwarz

et al. 2015

Neuron

170

199

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“…In contrast, Dox withdrawal induced miR-211 accumulation in the frontal cortex, hippocampus, and striatum, but not in the cerebellum (Fig. 2B), essentially as reported for other CamK:Tet mouse lines (35). When readministered with Dox, adult (2-mo-old) dTg-211 mice showed miR-211 decline to basal levels in the frontal cortex within 4 d (Fig.…”

Section: Dtg-211 Mice Present Spontaneous Emergence Of Nonconvulsivesupporting

confidence: 81%

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

Bekenstein

Mishra

Milikovsky

et al. 2017

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

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Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain micro-RNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergicmediated seizures by intersecting forebrain miR profiles that were Argonaute precipitated, synaptic vesicle target enriched, or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic antiinflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline-suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented nonconvulsive seizures, accompanied by forebrain accumulation of the convulsive seizures mediating miR-134. RNA sequencing demonstrated in doxycycline-treated dTg-211 cortices overrepresentation of synaptic activity, Ca 2+ transmembrane transport, TGFBR2 signaling, and cholinergic synapse pathways. Additionally, a cholinergic dysregulated mouse model overexpressing a miR refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases, and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hypersynchronization and nonconvulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and interference with epilepsy.

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“…Although there were subtle differences between responder lines, the core expression pattern we observed was largely consistent over time, between genders, and across distinct reporter crosses. Because this data may be valuable to other groups now working with this model, we have made our histological images publically available through an online atlas aimed at documenting reporter expression in several commonly used tTA driver lines (www.rbwb.org) (Odeh et al 2011). …”

Section: Discussionmentioning

confidence: 99%

“…No transgenic driver is perfectly restricted in space or time, and researchers must recognize these limitations and within those boundaries choose their tools and their experimental questions with care. We believe that online atlases like the one expanded here can help to guide these decisions (Boy et al 2006; Odeh et al 2011), especially when used with complementary tools such as the Allen Brain Atlas, GENSAT, and Cre-line databases (Gong et al 2007; Taniguchi et al 2011). These public access resources will increasingly play a role in neuroscientific research, as groups begin to probe anatomical and functional relationships between regions of the central nervous system at even greater levels of refinement.…”

Section: Discussionmentioning

confidence: 99%

“…The histological images they provide offer potential users a starting point from which to gauge the utility of each driver for their studies (Gong et al 2007). Given our particular interest in the tTA system for neuronal transgene expression, we have initiated an independent online atlas to provide high-resolution images of lacZ reporter expression from the most widely used tTA driver lines (Boy et al 2006; Odeh et al 2011). Recognizing the importance of entorhinal-restricted expression in the Nop-tTA line for past studies in both AD and memory, we now add this driver to our atlas within the Rodent Brain Workbench (www.rbwb.org).…”

Section: Introductionmentioning

confidence: 99%

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Transgene expression in the Nop-tTA driver line is not inherently restricted to the entorhinal cortex

et al. 2015

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The entorhinal cortex (EC) plays a central role in episodic memory and is among the earliest sites of neurodegeneration and neurofibrillary tangle formation in Alzheimer's disease. Given its importance in memory and dementia, the ability to selectively modulate gene expression or neuronal function in the EC is of widespread interest. To this end, several recent studies have taken advantage of a transgenic line in which the tetracycline transactivator (tTA) was placed under control of the neuropsin (Nop) promoter to limit transgene expression within the medial EC and pre-/parasubiculum. Although the utility of this driver is contingent on its spatial specificity, no detailed neuroanatomical analysis of its expression has yet been conducted. We therefore undertook a systematic analysis of Nop-tTA expression using a lacZ reporter and have made the complete set of histological sections available through the Rodent Brain Workbench tTA atlas, www.rbwb.org. Our findings confirm that the highest density of tTA expression is found in the EC and pre-/parasubiculum, but also reveal considerable expression in several other cortical areas. Promiscuous transgene expression may account for the appearance of pathological protein aggregates outside of the EC in mouse models of Alzheimer's disease using this driver, as we find considerable overlap between sites of delayed amyloid deposition and regions with sparse (β-galactosidase reporter labeling. While different tet-responsive lines can display individual expression characteristics, our results suggest caution when designing experiments that depend on precise localization of gene products controlled by the Nop-tTA or other spatially restrictive transgenic drivers.

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Atlas of transgenic Tet-Off Ca2+/calmodulin-dependent protein kinase II and prion protein promoter activity in the mouse brain

Cited by 21 publications

References 49 publications

Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a

Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

Transgene expression in the Nop-tTA driver line is not inherently restricted to the entorhinal cortex

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