ABSTRACT
Genetic studies have linked the primate-specific gene locus G72 to the development of schizophrenia and bipolar disorder. Transgenic mice carrying the entire gene locus express G72 mRNA in dentate gyrus (DG) and entorhinal cortex, causing altered electrophysiological properties of their connections. These transgenic mice exhibit behavioral alterations related to psychiatric diseases, including cognitive deficits that can be reversed by treatment with N-acetylcysteine, which was also found to be effective in human patients. Here, we show that G72 transgenic mice have larger excitatory synapses with an increased amount of N-methyl-d-aspartate (NMDA) receptors in the molecular layer of DG, compared with wild-type littermates. Furthermore, transgenic animals have lower number of dentate granule cells with a parallel, but an even stronger decrease in the number of excitatory synapses in the molecular layer. Importantly, we also show that treatment with N-acetylcysteine can effectively normalize all these changes in transgenic animals, resulting in a state similar to wild-type mice. Our results show that G72 transcripts induce robust alterations in the glutamatergic system at the synaptic level that can be rescued with N-acetylcysteine treatment.
Subject(s)
Carrier Proteins/genetics , Dentate Gyrus/metabolism , Entorhinal Cortex/metabolism , Schizophrenia/genetics , Acetylcysteine/pharmacology , Animals , Dentate Gyrus/drug effects , Dentate Gyrus/physiopathology , Entorhinal Cortex/drug effects , Entorhinal Cortex/physiopathology , Free Radical Scavengers/pharmacology , Humans , Intracellular Signaling Peptides and Proteins , Mice , Mice, Transgenic , RNA, Messenger/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Schizophrenia/metabolism , Synapses/metabolismABSTRACT
BACKGROUND AND PURPOSE: The prevalence of smoking in schizophrenia patients is exceptionally high; it is not known why but many researchers suggest that smoking constitutes a form of self-medication. Among the symptoms of schizophrenia that may be improved by nicotine are cognitive deficits. Hence, we studied the effects of long-term nicotine administration on cognition in a genetic animal model of schizophrenia susceptibility, G72-transgenic (G72Tg) mice. EXPERIMENTAL APPROACH: The effect of long-term nicotine or saline, administered by osmotic minipumps, on different cognitive domains was assessed in G72Tg mice and controls using a battery of behavioural tests. To investigate the mechanism underlying phenotypic differences, quantitative autoradiographic mapping of nACh receptor subtypes was performed in forebrain structures to explore effects of chronic nicotine exposure on nACh receptor density in wild-type (WT) and G72Tg mice. KEY RESULTS: Genotype significantly affected the cognitive effects of chronic nicotine administration. Whereas chronic nicotine disrupted cognitive performance in WT mice, it was effective at restoring impaired prepulse inhibition, working memory and social recognition in G72Tg mice. However, long-term spatial learning was further impaired by nicotine in transgenic animals. In contrast, associative learning was protected by G72-expression against the adverse nicotine effects seen in WT animals. G72-expression did not decisively influence nicotine-induced up-regulation of the α4ß2*subtype, whereas α7nACh receptor density was differentially altered by genotype or by a genotype·treatment interaction in specific brain areas, most notably hippocampal subregions. CONCLUSIONS AND IMPLICATIONS: Our data support the hypothesis that nicotine self-medication of schizophrenics improves cognitive symptoms, possibly by facilitating nicotine-induced α7nACh receptor activation in the hippocampus.
Subject(s)
Behavior, Animal/drug effects , Memory, Short-Term/drug effects , Nicotine/administration & dosage , Nicotinic Agonists/administration & dosage , Nootropic Agents/administration & dosage , Schizophrenia/drug therapy , Schizophrenic Psychology , Animals , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cognition/drug effects , Disease Models, Animal , Drug Administration Schedule , Genotype , Humans , Intracellular Signaling Peptides and Proteins , Mice , Mice, Transgenic , Neural Inhibition/drug effects , Phenotype , Prosencephalon/drug effects , Prosencephalon/metabolism , Recognition, Psychology/drug effects , Schizophrenia/diagnosis , Schizophrenia/genetics , Social Behavior , Time Factors , alpha7 Nicotinic Acetylcholine Receptor/agonists , alpha7 Nicotinic Acetylcholine Receptor/metabolismABSTRACT
Peroxisomes are subcellular organelles with important functions in lipid metabolism that are found in virtually all eucaryotic cells. The peroxisomal membrane contains a number of integral and peripheral membrane proteins involved in the import of peroxisomal matrix proteins and the transport of metabolites across the membrane. The most abundant peroxisomal membrane protein (Pmp) in rat peroxisomes is Pmp22, a 22 kDa protein of unknown function that is encoded by the Pxmp2 gene. To investigate the function of the Pxmp2 gene, we have initiated mouse knockout studies. The expression level of the Pxmp2 mRNA in mice was investigated by Northern blot analysis. Pxmp2 RNA was shown to be differentially expressed with highest expression levels in liver, kidney and in heart tissue. Comparison with other peroxisomal marker genes revealed that the expression of Pxmp2, Pmp70 (Pxmp1) and catalase was regulated independently. Using 5' and 3' RACE we have cloned the full-length cDNA of murine Pxmp2 which comprises 863 nucleotides and have isolated a genomic clone containing the entire murine Pxmp2. We have analyzed the complete intron/exon structure of the Pxmp2 gene which contains five exons spanning about 11 kb on the genomic clone. All intron/exon splice junctions conform to the GT/AG rule. Sequence analysis of the Pxmp2 5' flanking region revealed that it was devoid of a TATA box, but characteristic promoter elements were identified within 250 base pairs upstream of the transcriptional start site. Using a mouse/hamster radiation hybrid panel, Pxmp2 was localized on mouse chromosome 5 at 59 cM.
Subject(s)
Genes/genetics , Membrane Proteins/genetics , Animals , Blotting, Northern , Chromosome Mapping , Cloning, Molecular , Cricetinae , DNA/chemistry , DNA/genetics , DNA, Complementary/chemistry , DNA, Complementary/genetics , Gene Expression , Mice , Mice, Inbred BALB C , Mice, Inbred Strains , Molecular Sequence Data , Promoter Regions, Genetic , Sequence Analysis, DNA , Tissue DistributionABSTRACT
Continuing education (CE) opportunities for oncology nurses practicing at an advanced level are difficult to access. This article describes an ongoing educational effort to meet the needs of this target group in a midwestern state. Details of conference planning, implementation, and evaluation are included. A description of the screening process and program content is emphasized. This approach is applicable to a variety of specialty practice areas.
Subject(s)
Education, Nursing, Continuing/organization & administration , Oncology Nursing/education , Program Development , Curriculum , Humans , Program EvaluationABSTRACT
In order to gain insight into the quality of life from a patient perspective, individuals with cancer receiving home nursing care were given diaries to record the occurrence of health problems. On the average, health problems were reported on 35% of the recording days. Concerns related to somatic discomfort accounted for 76% of all health problems reported. Overall, digestive problems were the most commonly reported category of health problems. Those with lung cancer reported the highest average number of health problems per person (means = 9.3) and the greatest diversity of problems during the recording period. The results also suggest a common core of health problems important to cancer patients, with the relative importance of these problems varying by cancer diagnosis.
