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Persistent large-scale changes in alternative splicing in prefrontal cortical neuron types following psychedelic exposure

ABSTRACT: The goal of this project was to assess the cell-type specific transcriptomic changes induced by psychedelics in a rodent model. We used the RiboTag technique to isolate RNA from genetically-defined neuronal subtypes in the mouse prefrontal cortex. Conditional tagging of the ribosomal protein Rpl22 was done with Pvalb-Cre, Cux2-CreERT, and Rbp4-Cre for PV interneurons, L2/3 pyramidal neurons, and L5 pyramidal neurons respectively. We deep-sequenced (~100 million paired-end reads) the RNAs using Illumina platforms. We found cell-type specific gene expression and alternative splicing changes associated with psychedelics, providing a essential resource for understanding the various effects of psychedelics on cortical cell types and functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE286904 | GEO | 2025/01/16

REPOSITORIES: GEO

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Project description:Down syndrome (DS) is the most prevalent genetic abnormality, occurring in ~1/700 live births caused by triplication of human chromosome 21 (HSA21). DS individuals have a multitude of phenotypic changes in peripheral systems and most notably, are cognitively impaired, with deficits in learning, language and memory acquisition and consolidation. Further, individuals with DS develop Alzheimer’s disease (AD) pathology during early middle-age (mid-30’s), although the underlying mechanism(s) driving this pathology onset are not well understood. Contributing to cognitive impairment in DS, morphological deficits are present in cortical lamination and distribution, with Layer III (L3) and Layer V (L5) pyramidal neurons showing reduced proliferation and a disorganized laminar structure. As such, examining cortical L3 and L5 pyramidal neurons in DS individuals with AD pathology may elucidate alternate driver mechanisms of disease onset. We examined DS and age-matched control (CTR) brains from individuals without intellectual disabilities or dementia using postmortem frontal cortex (BA9) via single population low input RNA-sequencing. We specifically targeted L3 and L5 pyramidal neurons to understand circuitry-based alterations in DS/AD individuals to elucidate mechanistic drivers of disease pathology. We show convergent and divergent gene expression changes in L3 and L5 pyramidal neurons which may underlie cognitive deficits and degenerative pathology associated with aging in the DS brain. We pinpoint alterations in HSA21 gene expression as well as a multitude of convergent differentially expressed genes (DEGs) and relevant pathways via bioinformatic inquiry in the DS brains that underlie mechanisms of degeneration. Distinctly, convergent gene expression reveals a neurotoxic phenotype, with multiple canonical pathways of dysregulation and disease functions linked to the convergent DEGs, including downregulation of the CLEAR signaling pathway and significantly increased activation of the neuroinflammation signaling pathway. We identify several target genes including mitogen activated protein kinase 1 and 3 (MAPK1/3), calcium voltage-gated channel subunit alpha1 A (CACNA1A) and superoxide dismutase 1 (SOD1), which exhibit overlap in multiple pathways and disease functions and/or display dysfunctional protein-protein network interactions for further examination. Novel targets identified by our single population approach in L3 and L5 pyramidal neurons may be drivers of the disease mechanism and therefore may be therapeutic candidates for amelioration of degenerative pathology that targets memory and executive function circuits in DS/AD.

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Persistent large-scale changes in alternative splicing in prefrontal cortical neuron types following psychedelic exposure

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