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RNA expression across 6 strains of mice in relation to prepulse inhibition testing, as described in: Pdxdc1 (pyridoxal-dependent decarboxylase domain containing 1) modulates pre-pulse inhibition of acoustic startle in the mouse

ABSTRACT: C3H/HeJ, BalbC/J, C57BL/6J, C57BL10/J, C57BLKS/J, C57L/J strains were tested for variability in gene expression in hippocampus, striatal, and brainstem tissues to affiliate findings with behavioural prepulse inhibition scores Abstract: Current antipsychotic medications used to treat schizophrenia all target the dopamine D2 receptor. Although these drugs have serious side effects and limited efficacy, no novel molecular targets for schizophrenia treatment have been successfully translated into new medications. To identify novel potential treatment targets for schizophrenia, we searched for previously unknown molecular modulators of acoustic pre-pulse inhibition (PPI), a schizophrenia endophenotype, in the mouse. We examined six inbred mouse strains that have a range of PPI, and used microarrays to determine which mRNA levels correlated with PPI across these mouse strains. We examined several brain regions involved in PPI and schizophrenia: hippocampus, striatum and brainstem, and found transcripts that had good correlation with PPI level, and confirmed this with real-time quantitative PCR. We then selected one candidate gene for further study, Pdxdc1 (pyridoxal-dependent decarboxylase domain containing 1), because it is a putative enzyme that could metabolize catecholamine neurotransmitters, and thus might be a feasible target for new medications. We determined that Pdxdc1 mRNA and protein are both strongly expressed in the hippocampus and levels of Pdxdc1 are inversely correlated with PPI across the six mouse strains. Using shRNA packaged in a lentiviral vector, we suppressed Pdxdc1 protein levels in the hippocampus and increased PPI by at least 16%. Our results suggest that Pdxdc1 may regulate PPI and could be investigated further as a potential treatment target for schizophrenia.

ORGANISM(S): Mus musculus

PROVIDER: GSE97198 | GEO | 2017/03/30

SECONDARY ACCESSION(S): PRJNA380935

REPOSITORIES: GEO

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Project description:Post-transcriptional mechanisms play an important role in the control of gene expression. RNA-binding proteins are key players in the post-transcriptional control of many neural genes and they participate in multiple processes, from RNA splicing and mRNA transport to mRNA stability and translation. Our laboratory has developed the first mouse model overexpressing a RNA-binding protein, the ELAV-like protein HuD, in the CNS under the control of the CaMKinII alpha promoter. Initial behavioral characterization of the mice revealed that they had significant learning deficits together with abnormalities in prepulse inhibition (PPI). At the molecular level, we found that the expression of the growth-associated protein GAP-43, one of the targets of HuD, was increased in the hippocampus of HuD transgenic mice. To characterize these mice further and to evaluate the utility of these animals in understanding human diseases, we propose to use DNA microarray methods. To test our hypothesis we propose 2 specific aims: 1)To characterize the pattern of gene expression in the hippocampus of HuD overexpressor mice 2)To compare the pattern of gene expression in our mouse model with that in the hippocampus of rats prenatally exposed to alcohol (FAS model) and in post-mortem tissues of patients with schizophrenia; Based on the behavioral and molecular properties of our HuD transgenic mice we hypothesize that these animals may be good models for the studying the basis of learning disabilities and of diseases that show deficits in PPI such as fetal alcohol syndrome and schizophrenia. All mice are in C57BL/6 background and are male approximately 60 days old. Initial studies were performed in animals that were not subjected to any experimental manipulation. Animals were bred and sacrificed according to our approved animal protocol. The brain was rapidly dissected on ice and we isolated the hippocampus, which has the highest expression of the transgene. After dissection both hippocampi were frozen in liquid nitrogen, pooled and stored at -80°C until analysis. RNA samples were isolated using RNAeasy Qiagen columns. For our first experiment, we want to examine the pattern of gene expression in the hippocampus of 3 transgenic mice and 3 non-transgenic littermates. RNAs from the 6 hippocampi were of high quality as revealed by the integrity of the 28S and 18S rRNA. We will provide 6 samples containing 10 ug of RNA each in DEPC water at a concentration of about 0.5 ug/ul. Three of the samples (#1, #2 and #3) are from transgenic mice and three from their non-transgenic littermates (#4, #5 and #6).

Project description:Post-transcriptional mechanisms play an important role in the control of gene expression. RNA-binding proteins are key players in the post-transcriptional control of many neural genes and they participate in multiple processes, from RNA splicing and mRNA transport to mRNA stability and translation. Our laboratory has developed the first mouse model overexpressing a RNA-binding protein, the ELAV-like protein HuD, in the CNS under the control of the CaMKinII alpha promoter. Initial behavioral characterization of the mice revealed that they had significant learning deficits together with abnormalities in prepulse inhibition (PPI). At the molecular level, we found that the expression of the growth-associated protein GAP-43, one of the targets of HuD, was increased in the hippocampus of HuD transgenic mice. To characterize these mice further and to evaluate the utility of these animals in understanding human diseases, we propose to use DNA microarray methods. To characterize the pattern of gene expression in the hippocampus of HuD overexpressor mice; Based on the behavioral and molecular properties of our HuD transgenic mice we hypothesize that these animals may be good models for the studying the basis of learning disabilities and of diseases that show deficits in PPI such as fetal alcohol syndrome and schizophrenia. All mice are in C57BL/6 background and are male approximately 30 days old. Animals are bred and sacrificed according to our approved animal protocol. Brains will be rapidly dissected on ice, quickly frozen and stored at -80C until analysis. Frozen brains will be embedded in OCT and shipped to the DNA microarray facility at Duke University where LCM was performed. Dentate granule cells from control and HuD transgenic mice will be isolated by Susan Su, who will also perform RNA isolation and the first round of RNA amplification. For our first experiment, we want to examine the pattern of gene expression in the hippocampus of 2 transgenic mice and 2 non-transgenic littermates.

Project description:Our laboratory has developed the first mouse model overexpressing a RNA-binding protein, the ELAV-like protein HuD, in the CNS under the control of the CaMKinII alpha promoter. Initial behavioral characterization of the mice revealed that they had significant learning deficits together with abnormalities in prepulse inhibition (PPI). At the molecular level, we found that the expression of the growth-associated protein GAP-43, one of the targets of HuD, was increased in the hippocampus of HuD transgenic mice. To characterize these mice further and to evaluate the utility of these animals in understanding human diseases, we propose to use DNA microarray methods. To test our hypothesis we propose 3 specific aims: 1) To characterize the pattern of gene expression in the hippocampus of HuD overexpressor mice 2) To compare the pattern of gene expression in our mouse model with that in the hippocampus of rats prenatally exposed to alcohol (FAS model) and 3) To compare the pattern of gene expression in our mouse model with that shown in post-mortem tissues of patients with schizophrenia. In our previous protocols we examined the pattern of gene expression in our HuD transgenic mice and in rats prenaltally exposed to alcohol. A report by another group (Hakak et al, 2001) showed that three of the HuD targets were upregulated in the prefrontal cortex of patients with schizophrenia. To evaluate whether other target of HuD may be affected in this illness, in the current protocol, we want to compare the pattern of expression in our transgenic mice with in tissue from patients with schizophrenia Based on the behavioral and molecular properties of our HuD transgenic mice we hypothesize that these animals may be good models for the studying the basis of learning disabilities and of diseases that show deficits in PPI such as fetal alcohol syndrome and schizophrenia. All 28 samples are derived from cerebellar tissues for patients with schizophrenia and matched controls. The specimens were obtained from the Maryland Brain Collection according to NIH guidelines for confidentially and privacy. The protocol used in these studies was reviewed by our HRRC which found that our studies do not fall within the category of protocols monitored by the IRB (see attached letter form the HRRC). Specimens from 14 patients with a diagnosis of schizophrenia performed according to DSM-IV criteria and 14 sex-, age- and PMI-matched controls was included in this study. No differences were found between patients and control subjects in the average age (45±12 versus 43±10 years, p=0.86) or PMI (12±5 versus 16±6 hours, p=0.11). We will provide 28 samples containing 5 ug of RNA each in DEPC water (see validation of the quality of the RNA below). In addition, we include in our study animals treated with haloperidol as control for medication. These samples will be submitted in a separate protocol. Keywords: other

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RNA expression across 6 strains of mice in relation to prepulse inhibition testing, as described in: Pdxdc1 (pyridoxal-dependent decarboxylase domain containing 1) modulates pre-pulse inhibition of acoustic startle in the mouse

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