Dataset Information

Aberrant Cortical Ensembles and Schizophrenia-like Sensory Phenotypes in Setd1a^+/- Mice.

ABSTRACT:

Background

A breakdown of synchrony within neuronal ensembles leading to destabilization of network "attractors" could be a defining aspect of neuropsychiatric diseases such as schizophrenia, representing a common downstream convergence point for the diverse etiological pathways associated with the disease. Using a mouse genetic model, we demonstrated that altered ensembles are associated with pathological sensory cortical processing phenotypes resulting from loss of function mutations in the Setd1a gene, a recently identified rare risk genotype with very high penetrance for schizophrenia.

Methods

We used fast two-photon calcium imaging of neuronal populations (calcium indicator GCaMP6s, 10 Hz, 100-250 cells, layer 2/3 of primary visual cortex, i.e., V1) in awake head-fixed mice (Setd1a^+/- vs. wild-type littermate control) during rest and visual stimulation with moving full-field square-wave gratings (0.04 cycles per degree, 2.0 cycles per second, 100% contrast, 12 directions). Multielectrode recordings were analyzed in the time-frequency domain to assess stimulus-induced oscillations and cross-layer phase synchrony.

Results

Neuronal activity and orientation/direction selectivity were unaffected in Setd1a^+/- mice, but correlations between cell pairs in V1 showed altered distributions compared with wild-type mice, in both ongoing and visually evoked activity. Furthermore, population-wide "ensemble activations" in Setd1a^+/- mice were markedly less reliable over time during rest and visual stimulation, resulting in unstable encoding of basic visual information. This alteration of ensembles coincided with reductions in alpha and high-gamma band phase synchrony within and between cortical layers.

Conclusions

These results provide new evidence for an ensemble hypothesis of schizophrenia and highlight the utility of Setd1a^+/- mice for modeling sensory-processing phenotypes.

SUBMITTER: Hamm JP

PROVIDER: S-EPMC7363535 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDimeric human erythropoietin (dHuEPO) peptides are reported to exhibit significantly higher biological activity than the monomeric form of recombinant EPO. The objective of this study was to produce transgenic (tg) mice expressing dHuEPO and to investigate the characteristics of these mice.MethodsA dHuEPO-expressing vector under the control of the goat beta-casein promoter, which produced a dimer of human EPO molecules linked by a 2-amino acid peptide linker (Asp-Ile), was constructed and injected into 1-cell fertilized embryos by microinjection. Mice were screened using genomic DNA samples obtained from tail biopsies. Blood samples were obtained by heart puncture using heparinized tubes, and hematologic parameters were assessed. Using the microarray analysis tool, we analyzed differences in gene expression in the spleens of tg and control mice.ResultsA high rate of spontaneous abortion or death of the offspring was observed in the recipients of dHuEPO embryos. We obtained 3 founder lines (#4, #11, and #47) of tg mice expressing the dHuEPO gene. However, only one founder line showed stable germline integration and transmission, subsequently establishing the only transgenic line (#11). We obtained 2 F1 mice and 3 F2 mice from line #11. The dHuEPO protein could not be obtained because of repeated spontaneous abortions in the tg mice. Tg mice exhibited symptoms such as short lifespan and abnormal blood composition. The red blood cell count, white blood cell count, and hematocrit levels in the tg mice were remarkably higher than those in the control mice. The spleens of the tg mice (F1 and F2 females) were 11- and -21-fold larger than those of the control mice. Microarray analysis revealed 2,672 spleen-derived candidate genes; more genes were downregulated than upregulated (849/764). Reverse transcriptase-polymerase chain reaction (RT-PCR) and quantitative real-time PCR (qRT-PCR) were used for validating the results of the microarray analysis of mRNA expression.ConclusionsIn conclusion, dHuEPO tg mice caused excessive erythrocytosis that led to abnormal blood composition, short lifespan, and abnormal splenomegaly. Further, we identified 2,672 genes associated with splenomegaly by microarray analysis. These results could be useful in the development of dHuEPO-producing tg animals.

Dataset Information

Aberrant Cortical Ensembles and Schizophrenia-like Sensory Phenotypes in Setd1a^+/- Mice.

Background

Methods

Results

Conclusions

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Dataset Information

Aberrant Cortical Ensembles and Schizophrenia-like Sensory Phenotypes in Setd1a+/- Mice.

Background

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Aberrant Cortical Ensembles and Schizophrenia-like Sensory Phenotypes in Setd1a^+/- Mice.