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  • 1
    Keywords: brain ; RECEPTOR ; EXPRESSION ; Germany ; SYSTEM ; POPULATION ; DRUG ; LINES ; MICE ; RELEASE ; ACTIVATION ; RESPONSES ; MESSENGER-RNA ; BIOLOGY ; MOLECULAR-BIOLOGY ; TYPE-1 ; ACID ; DELETION ; knockout ; MOUSE ; NERVOUS-SYSTEM ; LINE ; POPULATIONS ; CENTRAL-NERVOUS-SYSTEM ; DISSECTION ; LACKING ; SUBPOPULATION ; molecular biology ; molecular ; LIBRARIES ; MICE LACKING ; NEURONS ; SUBSTRATE ; KNOCKOUT MICE ; USA ; function ; neuron ; central nervous system ; ENDOGENOUS CANNABINOIDS ; ADULT-MOUSE FOREBRAIN ; CB1 CANNABINOID RECEPTOR ; DISTINCT NEURONAL SUBPOPULATIONS ; ENDOCANNABINOID SYSTEM ; PRINCIPAL NEURONS ; SYNAPTIC-TRANSMISSION
    Abstract: Marijuana and its main psychotropic ingredient Delta(9)-tetrahydrocannabinol (THC) exert a plethora of psychoactive effects through the activation of the neuronal cannabinoid receptor type 1 (CB1), which is expressed by different neuronal subpopulations in the central nervous system. The exact neuroanatomical substrates underlying each effect of THC are, however, not known. We tested locomotor, hypothermic, analgesic, and cataleptic effects of THC in conditional knockout mouse lines, which lack the expression of CB1 in different neuronal subpopulations, including principal brain neurons, GABAergic neurons (those that release c aminobutyric acid), cortical glutamatergic neurons, and neurons expressing the dopamine receptor D1, respectively. Surprisingly, mice lacking CB1 in GABAergic neurons responded to THC similarly as wild-type littermates did, whereas deletion of the receptor in all principal neurons abolished or strongly reduced the behavioural and autonomic responses to the drug. Moreover, locomotor and hypothermic effects of THC depend on cortical glutamatergic neurons, whereas the deletion of CB1 from the majority of striatal neurons and a subpopulation of cortical glutamatergic neurons blocked the cataleptic effect of the drug. These data show that several important pharmacological actions of THC do not depend on functional expression of CB1 on GABAergic interneurons, but on other neuronal populations, and pave the way to a refined interpretation of the pharmacological effects of cannabinoids on neuronal functions
    Type of Publication: Journal article published
    PubMed ID: 17927447
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  • 2
    Keywords: brain ; EXPRESSION ; Germany ; human ; GENE ; transcription ; MICE ; PATIENT ; ACTIVATION ; TRANSCRIPTION FACTOR ; MARKER ; PHOSPHORYLATION ; ASSOCIATION ; polymorphism ; CAMP ; ELEMENT-BINDING PROTEIN ; PATTERNS ; CYCLIC-AMP ; molecular ; PATTERN ; LIGHT ; analysis ; MEDICINE ; CIRCADIAN CLOCK ; MAJOR DEPRESSION ; SUPRACHIASMATIC-NUCLEI
    Abstract: Activation of the transcription factor CREB by Ser142 phosphorylation is implicated in synchronizing circadian rhythmicity, which is disturbed in many depressive patients. Hence, one could assume that emotional behaviour and neuroendocrinological markers would be altered in CREBS142A mice, in which serine 142 is replaced by alanine, preventing phosphorylation at this residue. Moreover, associations of CREB Ser142 and seasonal affective disorder (SAD) might be detectable by the analysis of single-nucleotide polymorphisms (SNPs) in the CREB gene close to the Ser142 residue in SAD patients. However, neither CREBS142A mice demonstrate features of depression, nor there is evidence for an association of SAD with the CREB genotypes. Nevertheless, in humans there is an association of a global seasonality score and circadian rhythmicity with the CREB genotypes in healthy control probands, but not SAD patients. This parallels the phenotype of CREBS142A mice, presenting alterations of circadian rhythm and light-induced entrainment. Thus it is reasonable to assume that CREB Ser142 represents a molecular switch in mice and men, which is responsible for the (dys)regulation of circadian rhythms. (C) 2007 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17574346
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  • 3
    Keywords: recombination
    Type of Publication: Journal article published
    PubMed ID: 11848394
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  • 4
    Abstract: Biological rhythms are driven in mammals by a central circadian clock located in the suprachiasmatic nucleus (SCN). Light-induced phase shifting of this clock is correlated with phosphorylation of CREB at Ser133 in the SCN. Here, we characterize phosphorylation of CREB at Ser142 and describe its contribution to the entrainment of the clock. In the SCN, light and glutamate strongly induce CREB Ser142 phosphorylation. To determine the physiological relevance of phosphorylation at Ser142, we generated a mouse mutant, CREB(S142A), lacking this phosphorylation site. Light-induced phase shifts of locomotion and expression of c-Fos and mPer1 in the SCN are significantly attenuated in CREB(S142A) mutants. Our findings provide genetic evidence that CREB Ser142 phosphorylation is involved in the entrainment of the mammalian clock and reveal a novel phosphorylation-dependent regulation of CREB activity.
    Type of Publication: Journal article published
    PubMed ID: 11970866
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  • 5
    Keywords: brain ; CELLS ; EXPRESSION ; IN-VITRO ; Germany ; DENSITY ; SYSTEM ; GENE ; GENE-EXPRESSION ; transcription ; TRANSCRIPTION FACTOR ; PHOSPHORYLATION ; DELETION ; MOUSE ; NERVOUS-SYSTEM ; LIM-KINASE ; CELL-MIGRATION ; ACTIN CYTOSKELETON ; TARGET GENE ; TERNARY COMPLEX ; ACTIN DYNAMICS ; C-FOS PROMOTER ; cell migration ; cofilin ; FOREBRAIN ; SERUM RESPONSE FACTOR ; SRF ; TARGET GENES
    Abstract: The central nervous system is fundamentally dependent on guided cell migration, both during development and in adulthood. We report an absolute requirement of the transcription factor serum response factor (SRF) for neuronal migration in the mouse forebrain. Conditional, late-prenatal deletion of Srf causes neurons to accumulate ectopically at the subventricular zone (SVZ), a prime neurogenic region in the brain. SRF-deficient cells of the SVZ exhibit impaired tangential chain migration along the rostral migratory stream into the olfactory bulb. SVZ explants display retarded chain migration in vitro. Regarding target genes, SRF deficiency impairs expression of the beta-actin and gelsolin genes, accompanied by reduced cytoskeletal actin fiber density. At the posttranslational level, cofilin, a key regulator of actin dynamics, displays dramatically elevated inhibitory phosphorylation at Ser-3. Our studies indicate that SRIF-controlled gene expression directs both the structure and dynamics of the actin microfilament, thereby determining cell-autonomous neuronal migration
    Type of Publication: Journal article published
    PubMed ID: 15837932
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  • 6
    Keywords: ACAD, analysis, animal, animals, CELL, CELLS, CENTRAL-NERVOUS-SYSTEM, DISTINCT, EXPRESSION, fibrobla
    Abstract: Current methods to analyze gene expression measure steady-state levels of mRNA. To specifically analyze mRNA transcription, we have developed a technique that can be applied in vivo in intact cells and animals. Our method makes use of the cellular pyrimidine salvage pathway and is based on affinity-chromatographic isolation of thiolated mRNA. When combined with data on mRNA steady-state levels, this method is able to assess the relative contributions of mRNA synthesis and degradation/stabilization. It overcomes limitations associated with currently available methods such as mechanistic intervention that disrupts cellular physiology, or the inability to apply the techniques in vivo. Our method was first tested in serum response of cultured fibroblast cells and then applied to the study of renal ischemia reperfusion injury, demonstrating its applicability for whole organs in vivo. Combined with data on mRNA steady-state levels, this method provided a detailed analysis of regulatory mechanisms of mRNA expression and the relative contributions of RNA synthesis and turnover within distinct pathways, and identification of genes expressed at low abundance at the transcriptional level
    Type of Publication: Journal article published
    PubMed ID: 17405863
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  • 7
    Keywords: CELLS ; EXPRESSION ; MOUSE-BRAIN ; TRANSGENIC MICE ; CRE ; KeyWords Plus: SITE-SPECIFIC RECOMBINATION
    Abstract: We describe the generation of transgenic mouse lines expressing the Cre recombinase enzyme in brain under control of the CamKIIalpha gene present in a BAC expression vector. The CamKIIalpha BAC transgene gave a faithful expression pattern resembling the pattern of the endogenous CamKIIalpha gene. Specifically, high levels of CamKIIalpha Cre were detected in hippocampus, cortex, and amygdala, and lower levels were detected in striatum, thalamus, and hypothalamus. As expected, no expression was detected in the cerebellum or outside of the brain. The expression level of the BAC CamKIIalpha driven Cre was shown to be copy number dependent. To test the activity of the Cre recombinase, the transgenic mice were crossed with mice harbouring the CREB (cAMP response element binding protein) allele with the 10th exon flanked by two loxP sites, and recombination was monitored by the disappearance of the CREB protein. Finally, evaluation of the developmental postnatal expression of the CamKIIalpha Cre BAC revealed the expression of the Cre recombinase as early as P3.
    Type of Publication: Journal article published
    PubMed ID: 11668676
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  • 8
    Keywords: brain ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; MODEL ; VITRO ; SYSTEM ; NEW-YORK ; GENE ; GENOME ; PROTEIN ; recombination ; ALPHA ; MOUSE ; PROMOTER ; PROMOTERS ; inactivation ; BETA ; alpha complementation,iCre recombinase,IoxP ; COMPLEMENTATION ; POLYPEPTIDE ; SITE-SPECIFIC RECOMBINATION
    Abstract: The Cre-IoxP system is increasingly exploited for spatial and temporal gene inactivation. Here we present a novel approach to achieve this goal of selective gene inactivation. Following the model of complementation in the beta-galactosidase enzyme, where the enzyme is split into independent polypeptides which are able to associate and maintain the enzymatic activity, we divided the Cre recombinase into two independent polypeptides (one containing the NH2 terminus (alpha) and a second one containing the COOH-terminus (beta)). Individually, the two polypeptides have no detectable activity. However, when coexpressed the polypeptides are able to associate, giving rise to Cre enzymatic activity, which optimally is as high as 30% of that seen with wildtype Cre recombinase in vitro. We present this strategy as a modification of the traditional Cre-IoxP system, which could be used to obtain a highly specific recombination pattern by expressing the two halves under the control of separate promoters. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 14502574
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  • 9
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; SYSTEM ; EXPOSURE ; PROTEIN ; PROTEINS ; MICE ; RELEASE ; ACTIVATION ; FAMILY ; REDUCTION ; INDUCTION ; RAT ; MEMBER ; MEMBERS ; SIGNAL ; NERVOUS-SYSTEM ; immunohistochemistry ; c-Fos ; DISPLAY ; REGION ; GENOTYPES ; STIMULI ; REGIONS ; NUCLEUS ; CENTRAL-NERVOUS-SYSTEM ; RECEPTORS ; BEHAVIOR ; ALPHA-SUBUNIT ; INITIATION ; LACKING ; MOTOR ; MAMMARY-GLAND ; NEURONS ; CEREBELLAR PURKINJE-CELLS ; ESTROGEN ; FEMALE MICE ; G-ALPHA-Q ; NULL MUTATION ; OXYTOCIN RECEPTORS ; PROLACTIN RECEPTOR GENE
    Abstract: Heterotrimeric G proteins of the G(q/11) family transduce signals from a variety of neurotransmitter receptors and have therefore been implicated in several functions of the central nervous system. To investigate the potential role of G(q/11) signaling in behavior, we generated mice which lack the alpha-subunits of the two main members of the G(q/11) family, Galpha(q) and Galpha(11), selectively in the forebrain. We show here that forebrain Galpha(q/11)-deficient females do not display any maternal behavior such as nest building, pup retrieving, crouching, or nursing. However, olfaction, motor behavior and mammary gland function are normal in forebrain Galpha(q/11)-deficient females. We used c-fos immunohistochemistry to investigate pup-induced neuronal activation in different forebrain regions and found a significant reduction in the medial preoptic area, the bed nucleus of stria terminalis, and the lateral septum both in postpartum females and in virgin females after foster pup exposure. Pituitary function, especially prolactin release, was normal in forebrain Galpha(q/11)-deficient females, and activation of oxytocin receptor-positive neurons in the hypothalamus did not differ between genotypes. Our findings show that G(q/11) signaling is indispensable to the neuronal circuit that connects the perception of pup-related stimuli to the initiation of maternal behavior and that this defect cannot be attributed to either reduced systemic prolactin levels or impaired activation of oxytocin receptor-positive neurons of the hypothalamus
    Type of Publication: Journal article published
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  • 10
    Keywords: brain ; EXPRESSION ; SURVIVAL ; MODEL ; PATHWAY ; PATHWAYS ; SYSTEM ; POPULATION ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; MICE ; MECHANISM ; FAMILY ; CONTRAST ; mechanisms ; BINDING ; DELETION ; ELEMENT-BINDING PROTEIN ; NERVOUS-SYSTEM ; RESPONSE ELEMENT ; TRANSCRIPTION FACTORS ; gene expression ; c-Fos ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; Jun ; CRE RECOMBINASE ; BINDING PROTEIN ; signaling ; SERUM ; BINDING-PROTEIN ; ADULT ; regulation ; SERUM RESPONSE FACTOR ; SRF ; EVENTS ; HIPPOCAMPAL-NEURONS ; IMMEDIATE-EARLY GENES ; NMDA RECEPTOR ACTIVATION
    Abstract: Synaptic activity-dependent gene expression is critical for certain forms of neuronal plasticity and survival in the mammalian nervous system, yet the mechanisms by which coordinated regulation of activity-induced genes supports neuronal function is unclear. Here, we show that deletion of serum response factor (SRF) in specific neuronal populations in adult mice results in profound deficits in activity-dependent immediate early gene expression, but components of upstream signaling pathways and cyclic AMP - response element binding protein ( CREB)- dependent transactivation remain intact. Moreover, SRF-deficient CA1 pyramidal neurons show attenuation of long-term synaptic potentiation, a model for neuronal information storage. Furthermore, in contrast to the massive neurodegeneration seen in adult mice lacking CREB family members, SRF-deficient adult neurons show normal morphologies and basal excitatory synaptic transmission. These findings indicate that the transcriptional events underlying neuronal survival and plasticity are dissociable and that SRF plays a prominent role in use-dependent modification of synaptic strength in the adult brain
    Type of Publication: Journal article published
    PubMed ID: 15880109
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