Hippocampal Subfield Transcriptome Analysis in Schizophrenia Psychosis
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ABSTRACT: We have previously demonstrated functional and molecular changes in hippocampal subfields in individuals with schizophrenia (SZ) psychosis associated with hippocampal excitability. In this study, we use RNA-seq and assess global transcriptome changes in the hippocampal subfields, DG, CA3, and CA1 from individuals with SZ psychosis and controls to elucidate subfield-relevant molecular changes. We also examine changes in gene expression due to antipsychotic medication in the hippocampal subfields from our SZ ON- and OFF-antipsychotic medication cohort. We identify unique subfield-specific molecular profiles in schizophrenia postmortem samples compared to controls, implicating astrocytes in DG, immune mechanisms in CA3, and synaptic scaling in CA1. We show a unique pattern of subfield-specific effects by antipsychotic medication on gene expression levels with scant overlap of genes differentially expressed by SZ disease effect versus medication effect. These hippocampal subfield changes could provide the basis for previously observed hippocampal SZ pathology and explain the lack of full efficacy of conventional antipsychotic medication on SZ symptomatology. With further characterization, the identified distinct molecular profiles of the DG, CA3, and CA1 in SZ psychosis may serve to identify potential hippocampal-based therapeutic targets.
Project description:Purpose: In this study, we used LCM and RNA-Seq to characterize differences in the rat hippocampal expression profiles of CA1, CA2, CA3, and DG subfields Methods: Each subfield was bilaterally laser microdissected, collected from the rat's hippocampus (n=4), and submitted to Illuminas for massively parallel sequencing. Results: We found evident segregation of the transcriptomic profile from different regions of the hippocampus. Gene ontology enrichment analysis of CA1 subfield results in actin regulation genes and postsynaptic membrane AMPA receptors that are indispensable for long-term potentiation and learning and memory. CA2 and CA3 transcripts were found associated with the higher metabolic processes. DG expression was enriched for ribosome and spliceosome, both required for protein synthesis and maintenance of cell life. Conclusion: The present findings contribute to a deeper understanding of the differences in the molecular machinery expressed by the rat hippocampal neuronal populations, further exploring underlying mechanisms responsible for each subflied specific functions.
Project description:Hippocampus has drawn an immense attention from researchers and clinicians worldwide due to its clinical importance in various neurodegenerative disorders. Each hippocampal subfield is known to perform distinct functions and are selectively vulnerable to environmental, physiological, and clinical factors. Therefore, proteomic analysis of hippocampus at subfield level is increasingly important, however, an in-depth proteomic analysis of human hippocampus at its subfield level is not well established to date. In this study, we compared the sub-proteome of the hippocampus- the cornu ammonis sectors (CA1, CA2, CA3 and CA4), and dentate gyrus (DG) from healthy adult human cohorts using high resolution mass spectrometry. We procured hippocampal subfields from the archived FFPE tissue sections by performing manual micro-dissection and conducted TMT label quantification-based proteomic analysis that resulted in the identification of 5,593 proteins, of which 890 proteins were differentially abundant at ≥1.5-fold cut-off across all subfields. Gene Ontology enrichment analysis was performed to uncover the biological processes, pathways and cellular localization associated with each subfield of hippocampus. IHC-based validation of selected proteins were also carried out in an independent set of hippocampus from normal subjects. We believe that our findings will effectively pave a way for further analysis of the hippocampal subdivisions and understand the etiopathology of many neurological disorders in future.
Project description:Aging is associated with a decline in hippocampal mediated learning and memory, a process which can be ameliorated by dietary (caloric) restriction. We used Affymetrix gene expression analysis to monitor changes in three regions of the hippocampus (CA1, CA3, DG) of middle aged (18 months) and old (28 month) rats that were exposed to dietary restriction. Old rats were determined to be good performers (GP) or poor performers (PP) in behavioural tests to assess their hippocampal function. We used Affymetrix gene expression analysis to monitor changes in three regions of the hippocampus (CA1, CA3, DG) of middle aged (18 months) and old (28 month) rats that were exposed to dietary restriction.
Project description:This SuperSeries is composed of the following subset Series:; GSE11473: Rapid encoding of information alters the profile of plasticity related mRNA transcripts in the hippocampal CA3 region; GSE11474: Rapid encoding of information alters the profile of plasticity related mRNA transcripts in the hippocampal CA1 region. GSE11475: Rapid encoding of information alters the profile of plasticity related mRNA transcripts in the hippocampal DG region Experiment Overall Design: Refer to individual Series
Project description:The project examined age-related change in hippocampal gene expression in Fisher 344 x Brown Norway F1 rats from the NIA aging colony (Adult = 12M, Aged = 24M). CA1, CA3, and DG specific dissections were examined from one cohort of animals and from a second cohort whole hippocampus was used. Hippocampal gene expression with aging in a rat model was examined between Adult (12M) and Aged animals (24M)
Project description:The project examined age-related change in hippocampal gene expression in Fisher 344 x Brown Norway F1 rats from the NIA aging colony (Adult = 12M, Aged = 24M). CA1, CA3, and DG specific dissections were examined from one cohort of animals and from a second cohort whole hippocampus was used.
Project description:MicroRNAs (miRNAs) are short noncoding RNAs that shape the gene expression landscape, including during the pathogenesis of temporal lobe epilepsy (TLE). In order to provide a full catalog of the miRNA changes that happen during experimental TLE, we sequenced Argonaute 2-loaded miRNAs in CA1, CA3 and Dentate Gyrus hippocampal subfields from the rat perforant pathway stimulation (PPS) model at regular intervals between the time of the initial precipitating insult to the establishment of spontaneous recurrent seizures.
Project description:Single-neuron gene expression studies may be especially important for understanding nervous system structure and function because of the neuron-specific functionality and plasticity that defines functional neural circuits. Cellular dissociation is a prerequisite technical manipulation for single-cell and single cell-population studies, but the extent to which the cellular dissociation process affects neural gene expression has not been determined. This information is necessary for interpreting the results of experimental manipulations that affect neural function such as learning and memory. The goal of this research was to determine the impact of chemical cell dissociation on brain transcriptomes. We compared gene expression of microdissected samples from the dentate gyrus (DG), CA3, and CA1 subfields of the mouse hippocampus either prepared by a standard tissue homogenization protocol or subjected to a chemical cellular dissociation procedure. We report that compared to homogenization, chemical cellular dissociation alters about 350 genes or 2% of the hippocampal transcriptome. While only a few genes canonically implicated in long-term potentiation (LTP) and fear memory change expression levels in response to the dissociation procedure, these data indicate that sample preparation can affect gene expression profiles, which might confound interpretation of results depending on the research question. This study is important for the investigation of any complex tissues as research effort moves from subfield level analysis to single cell analysis of gene expression.
Project description:Aging is associated with a decline in hippocampal mediated learning and memory, a process wich can be ameliorated by dietary (caloric) restriction. We used Affymetrix gene expression analysis to monitor changes in three regions of the hippocampus (CA1, CA3, DG) of middle aged (18 months) and old (28 month) rats that were exposed to dietary restriction. Old rats were determined to be good performers (GP) or poor performers (PP) in behavioral tests to assess thier hippocampal function.