Dataset Information

Expression profiles of the hippocampus of Rsk2-KO mice

ABSTRACT: Coffin–Lowry Syndrome (CLS) is a syndromic form of mental retardation caused by loss of function mutations in the X-linked RPS6KA3 gene, which encodes Rsk2, a serine/threonine kinase involved in spatial memory. We analyzed hippocampal gene expression profiles in Rsk2-KO mice to identify changes in molecular pathways. Total RNA was extracted from hippocampi from 6 KO and 6 WT (littermates) 2-month-old male mice. For each genotype, equivalent amounts of RNA from 2 mice were pooled and processed for hybridization to the genome wide oligonucleotide microarray (Murine 430A 2.0 Affymetrix, 22.000 probe sets). Thus, 3 independent pooled samples were hybridized for each genotype. We compared hippocampal gene expression profiles from rsk2-KO and normal littermate mice to identify changes in molecular pathways

ORGANISM(S): Mus musculus

SUBMITTER: André Hanauer Nathalie Rouach Tahir Mehmood Mohamed Ammar Patricia Marques-Pereira Jérémie Sibillec Anne Schneider Solange Pannetier Doulaye Dembele Christelle Thibault-Carpentier

PROVIDER: E-GEOD-22137 | ArrayExpress | 2010-12-22

SECONDARY ACCESSION(S): GSE22137PRJNA127575

REPOSITORIES: GEO, ArrayExpress

ACCESS DATA

Publications

Transcriptome profile reveals AMPA receptor dysfunction in the hippocampus of the Rsk2-knockout mice, an animal model of Coffin-Lowry syndrome.

Mehmood Tahir T Schneider Anne A Sibille Jérémie J Marques Pereira Patricia P Pannetier Solange S Ammar Mohamed Raafet MR Dembele Doulaye D Thibault-Carpentier Christelle C Rouach Nathalie N Hanauer André A

Human genetics 20101130 3

Coffin-Lowry syndrome (CLS) is a syndromic form of mental retardation caused by loss of function mutations in the X-linked RPS6KA3 gene, which encodes RSK2, a serine/threonine kinase acting in the MAPK/ERK pathway. The mouse invalidated for the Rps6ka3 (Rsk2-KO) gene displays learning and long-term spatial memory deficits. In the current study, we compared hippocampal gene expression profiles from Rsk2-KO and normal littermate mice to identify changes in molecular pathways. Differential expressi ...[more]

PMID: 21116650

Similar Datasets

Project description:Basic helix loop helix enhancer 40 (Bhlhe40) is a transcription factor expressed in rodent hippocampus, however, its role in neuronal function is not well understood. Here, we used Bhlhe40 null mice on a congenic C57Bl6/J background (Bhlhe40 KO) to investigate the impact of Bhlhe40 on neuronal excitability and synaptic plasticity. A whole genome expression array predicted that Bhlhe40 KO mice have up-regulated insulin-related pathways and down-regulated neuronal signaling-related pathways in the hippocampus. We validated that insulin degrading enzyme mRNA (Ide) and IDE protein are significantly downregulated in Bhlhe40 KO hippocampi. No significant difference was observed in hippocampal insulin levels. In hippocampal slices, we found CA1 neurons have increased miniature excitatory post-synaptic current (mEPSC) amplitude and decreased inhibitory post-synaptic current (IPSC) amplitude, indicating hyper-excitability in CA1 neurons in Bhlhe40 KO mice. At CA1 synapses, we found a reduction in long term potentiation (LTP) and long term depression (LTD), indicating an impairment in hippocampal synaptic plasticity in Bhlhe40 KO hippocampal slices. Bhlhe40 KO mice displayed no difference in seizure response to the convulsant kainic acid (KA) relative to controls. We found that while Bhlhe40 KO mice have decreased exploratory behavior they do not display alterations in spatial learning and memory. Together this suggests that Bhlhe40 plays a role in modulating neuronal excitability and synaptic plasticity ex vivo, however, Bhlhe40 alone does not play a significant role in seizure susceptibility and learning and memory in vivo. In addition, based on the reduction in IDE protein levels in these mice, there may be dysregulation of other known IDE substrates, namely insulin growth factor (Igf)-1, Igf-2, and Amyloid beta (Aβ). Overall design: Hippocampus, cortex, and cerebellum was examined from naïve 3-5 month old WT (n=4/tissue) and Bhlhe40 KO (n=4/tissue) mice.

Project description:We compare here the neurodegenerative processes observed in the hippocampus of bitransgenic mice with chronically altered levels of cAMP-response element-binding protein (CREB) function. The combination of genome-wide transcriptional profiling of degenerating hippocampal tissue with microscopy analyses reveals that the sustained inhibition of CREB function in A-CREB mice is associated with dark neuron degeneration, whereas its strong chronic activation in VP16-CREB mice primarily causes excitotoxic cell death and inflammation. Furthermore, the meta-analysis with gene expression profiles available in public databases identifies relevant common markers to other neurodegenerative processes and highlights the importance of the immune response in neurodegeneration. Overall, these analyses define the ultrastructural and transcriptional signatures associated with these two forms of hippocampal neurodegeneration, confirm the importance of fine-tuned regulation of CREBdependent gene expression for CA1 neuron survival and function, and provide novel insight into the function of CREB in the etiology of neurodegenerative processes. Overall design: For each mouse genome 430 2.0 gene expression array (Affymetrix, Santa Clara, CA, USA), total RNA was extracted from the hippocampi of three to four mice with the same age, sex, and genotype to produce one pooled sample. We analyzed three late A-CREB pooled samples (6-week-old mice) and three late VP16-CREB pooled samples (3-week-off dox) with their corresponding control littermate samples (three pooled samples for each strain). To compare with early changes, we included two pooled A-CREB early samples (3-week-old mice) and two pooled VP16-CREB early samples (1-week-off dox) with their corresponding control littermate samples. In the case of A-CREB mice, we used the dataset GSE14320. We prepared new samples from bitransgenic mice and control littermates 1 week after transgene induction and hybridized them to mouse genome 430 2.0 genechips. The arrays were hybridized, washed, and screened for quality according to the manufacturer’s protocol.

Project description:Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. The Dcx protein plays a key role in neuronal migration, and hippocampal pyramidal neurons in Dcx knockout (KO) mice are disorganized. The single CA3 pyramidal cell layer observed in wild type (WT) is present as two abnormal layers in the KO, and CA3 KO pyramidal neurons are more excitable than WT. Dcx KO mice also exhibit spontaneous epileptic activity originating in the hippocampus. It is unknown however, how hyperexcitability arises and why two CA3 layers are observed. Transcriptome analyses were performed to search for perturbed postnatal gene expression, comparing Dcx KO CA3 pyramidal cell layers with WT. Gene expression changes common to both KO layers indicated mitochondria and Golgi apparatus anomalies, as well as increased cell stress. Intriguingly, gene expression analyses also suggested that the KO layers differ significantly from each other, particularly in terms of maturity. Layer-specific molecular markers and BrdU birthdating to mark the final positions of neurons born at distinct timepoints revealed inverted layering of the CA3 region in Dcx KO animals. Notably, many early-born ‘outer boundary’ neurons are located in an inner position in the Dcx KO CA3, superficial to other pyramidal neurons. This abnormal positioning likely affects cell morphology and connectivity, influencing network function. Dissecting this Dcx KO phenotype sheds light on coordinated developmental mechanisms of neuronal subpopulations, as well as gene expression patterns contributing to a bi-layered malformation associated with epilepsy. Expression profiling by array Overall design: 15 laser microdissection samples analyzed corresponding to 5 wild type mouse brain hippocampi CA3 region, 5 doublecortin knockout mouse brain hippocampi internal part of CA3 region and from the same 5 knockout animals, mouse brain hippocampi external part of CA3 region