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Myeloid cell deficiency of the inflammatory transcript factor STAT4 protects long-term synaptic plasticity from the effects of a high-fat, high-cholesterol diet

ABSTRACT: Neuroinflammation is associated with neurodegenerative diseases, including Alzheimer’s and Parkinson’s. The cytokine interleukin-12 activates signal transducer and activator of transcription 4 (Stat4), consumption of a high-fat, high-cholesterol diet (HFD-C) and Stat4 activity are associated with inflammation, atherosclerosis, and a diabetic metabolic phenotype. In studies of in vitro hippocampal slices from control Stat4fl/flLdlr-/- mice fed a HFD-C diabetogenic diet, we found that Schaffer collateral-CA1 synapses exhibited larger reductions in activity-dependent, long-term potentiation (LTP) of synaptic transmission, compared to mice fed a standard diet. Glucose tolerance and insulin sensitivity shifts produced by HFD-C diet were reduced in Stat4ΔLysMLdlr-/- mice compared to Stat4fl/flLdlr-/- controls. Stat4ΔLysMLdlr-/- mice, which lack Stat4 under control of the LysMCre promoter, were resistant to HFD-C induced impairments in LTP. In contrast, Schaffer collateral-CA1 synapses in Stat4ΔLysMLdlr-/- mice fed the HFD-C diet showed larger LTP than control Stat4fl/flLdlr-/- mice. Expression of a number of neuroinflammatory and synaptic plasticity genes was reduced by HFD-C diet in control mice, and less affected by HFD-C diet in Stat4ΔLysMLdlr-/- mice. Suppression of Stat4 activation has potential for protecting against effects of western diet on cognition, type 2 diabetes, and reduce risk of Alzheimer’s disease and other neurodegenerative disorders associated with neuroinflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE240045 | GEO | 2023/09/01

REPOSITORIES: GEO

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Project description:Expression of VP16-CREB, a constitutively active form of CREB, in hippocampal neurons of the CA1 region lowers the threshold for eliciting the late, persistent phase of long-term potentiation (L-LTP) in the Schaffer collateral pathway. This VP16-CREB-mediated L-LTP differs from the conventional late phase of LTP in not being dependent on new transcription. This finding suggests that in the transgenic mice the mRNA transcript(s) encoding the protein(s) necessary for this form of L-LTP might already be present in CA1 neurons in the basal condition. We used high-density oligonucleotide arrays to identify the mRNAs differentially expressed in the hippocampus of transgenic and wild-type mice. Experiment Overall Design: To identify the specific gene whose induction in hippocampal neurons correlated with the facilitated L-LTP phenotype, we harvested hippocampal mRNA at time points assessed in our physiological study and carried out a gene expression analysis using oligonucleotide microarrays. To obtain a sufficient quantity of poly(A)-RNA and reduce the effect of the biological variability of the sample, hippocampi from 6 to 10 mice matched for genotype and time of induction were pooled together in each sample. The final data set included genechips for animals on dox (gene Off) and for animals that were one, two, and five weeks after removal of dox (gene On). We also included samples from wild-type mice maintained under identical conditions and from transgenic mice that expressed VP16-CREB for three weeks before turning the transgene off again for two weeks with dox (Rev, gene Off). Since the isolation of mRNA from the whole hippocampus favors genes that are more broadly over-expressed in the hippocampus of transgenic mice and, therefore, may lead to an underestimation of the total complement of genes showing an altered expression in specific hippocampal subregions, we extended our comparison between transgenic and wild-type expression profiles using microdissected CA1 regions. We obtained two samples corresponding to VP16-CREB mice three weeks after induction and one sample corresponding to wild-type mice kept in the same conditions. Experiment Overall Design: These twelve mRNA samples were analyzed using Affymetrix genechips MG-U74v2 setA.

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Myeloid cell deficiency of the inflammatory transcript factor STAT4 protects long-term synaptic plasticity from the effects of a high-fat, high-cholesterol diet

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