Comt is acknowledged to get also expressed in embryonic mouse brain,24 and DA receptor KO mice demonstrate abnormal morphology of dendrites of PFC projection neurons, greater parvalbumin expression inPFC interneurons and reduced mesencephalic dopaminergic neurons.25,26 These data may possibly propose a probability that Comt affects functioning memory and recognition memory via the regulation of neurodevelopmental practice. To address irrespective of whether grownup functions of Comt is responsible for behavioral defects in Df1/t mice, 1 of 22q11DS model mice,5 we examined the therapeutic likely of lentivirus-mediated Comt overexpression while in the grownup PFC of Df1/t mice. The DA agonists and N-methyl-D-aspartate receptor antagonists this kind of as Dizocilpine are acknowledged to possess psychometric effects on healthful individuals, and exacerbate signs and symptoms of schizophrenia patients.29?31 In Df1/t mice, the locomotor response to MK801 remedy was drastically enhanced ; kinase 1a). A single on the primary pathologies observed in schizophrenia is often a deficit in GABA signaling.
32?34 At first, to investigate a potential involvement of GABA signaling from the behavioral abnormality of Df1/t mice, we examined the impact of the nonselective GABAA partial receptor agonist, bretazenil. Bretazenil at 10mgkgu1 normalized the enhanced response of Df1/t mice to MK801 . In contrast, in management mice, bretazenil had no impact over the traveled distance during 60 min immediately after administration phenylalanine hydroxylase inhibitor . Following, to analyze which sort of GABAA receptor is responsible for this reversing result of bretazenil, Df1/t mice were handled with selective GABA agonists. SL651498, a selective agonist of GABAA a2/a3 receptor, but neither zolpidem, a selective agonist of GABAA a1 receptor, nor L655708, a selective inverse agonist of GABAA a5 receptor, especially reversed the enhanced response of Df1/t mice to MK801 .
Taken together, our information demonstrated that Salicin Df1/t mice display higher responsiveness to MK801 like human schizophrenic sufferers, plus the GABAergic transmission by GABAA a2/a3 receptor may well be involved with this abnormal behavioral phenotype of Df1/t mice. Yet, the deleted region of Df1/t mice is smaller sized than 1.5-Mb deletion found in human 22q11DS, which doesn’t incorporate Dgcr2 . Just lately, it’s been reported that a potentially destructive de-novo mutation was found in Dgcr2 inside a human schizophrenic patient,35 which suggests a doable involvement of Dgcr2 while in the pathogenesis of schizophrenia. To examine whether or not Dgcr2 haplodeletion also leads to behavioral abnormalities just like that in Df1/t mice, we genetically engineered Dgcr2 KO mice by homologous recombination in embryonic stem cells.
To introduce a targeted mutation in the mouse Dgcr2 gene, we constructed a targeting vector, by which the expression cassette of EGFP-SV40 polyA and also the neomycin resistance gene was inserted in exon one, which incorporates an initiation codon of Dgcr2 and flanked through the 50 five.6-kb and 30 one.2-kb Dgcr2 gene fragments .