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Cell type specific transcriptomic alterations in prefrontal deep-layer pyramidal neurons in individuals with a history of childhood abuse

ABSTRACT: Childhood abuse significantly increases the lifetime risk of negative mental health outcomes, including psychiatric disorders, such as depression and suicide. While clinical and epidemiological associations are well characterized, the molecular mechanisms through which adverse experiences in early life influence mental health outcomes over the lifespan remain unclear. In this study, we employed laser capture microdissection followed by RNA sequencing (LCM-seq) to investigate transcriptomic alterations to prefrontal deep-layer pyramidal neurons in individuals with a history of childhood abuse (N=24) in comparison to controls (N = 21). We first showed that LCM-seqproduced high-quality transcriptomic data that was strongly enriched for our cell type of interest (95.8% contribution). Differential expression analysis revealed119 genes that were altered between cases versus controls. Using weighted correlation network analysis (WGCNA) we next identified a network of downregulated genes, in individuals with a history of childhood abuse (r = -0.30, p = 0.04), that was enriched in pathways related to nervous system development and plasticity. The eigengene of this network was significantly correlated (r(23) = 0.490, p = 0.021) with average cell body volume of deep-layer pyramidal neurons. Of the 1042 mRNA genes within this network, 81 were differentially expressed between cases and controls. Using high-throughput qPCR, and comparing with an additional group of depressed subjects who died by suicide without a history of childhood abuse (N = 29), we found 7 genes whose expression levels were significantly (p < 0.05) predicted by a history of childhood abuse but not major depressive disorder and suicide.Our study, therefore, advances our understanding of the long term impact of childhood abuse and points to some of the molecular pathways that may underly previously observed alterations innervous system development and plasticity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157197 | GEO | 2022/12/30

REPOSITORIES: GEO

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Project description:Gray matter volume in the cerebral cortex has been consistently found to be decreased in patients with schizophrenia. The superior temporal gyrus (STG) is one of the cortical regions that exhibit the most pronounced volumetric reduction. This reduction is generally thought to reflect, at least in part, decreased number of synapses; the majority of these synapses are believed to be furnished by glutamatergic axon terminals onto the dendritic spines on pyramidal neurons. Pyramidal neurons in the cerebral cortex exhibit layer-specific connectional properties, providing neural circuit structures that support distinct aspects of higher cortical functions. For instance, dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex are targeted by both local and long-range glutamatergic projections in a highly reciprocal fashion. Synchronized activities of pyramidal neuronal networks, especially in the gamma frequency band (i.e. 30-100 Hz), are critical for the integrity of higher cortical functions. Disturbances of these networks may contribute to the pathophysiology of schizophrenia by compromising gamma oscillation. This concept is supported by the following postmortem and clinical observations. First, the density of dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex, including the STG, have been shown to be significantly decreased by 23-66% in subjects with schizophrenia. Second, consistent with these findings, the average somal area of these pyramidal cells is significantly smaller. Third, we have recently found that, in the prefrontal cortex, the density of glutamatergic axonal boutons, of which dendritic spines are their major targets, was significantly decreased by as much as 79% in layer 3 (but not layer 5) in subjects with schizophrenia. Finally, an increasing number of clinical studies have consistently demonstrated that gamma oscillatory synchrony is profoundly impaired in patients with schizophrenia. Furthermore, gamma impairment has been linked to the symptoms and cognitive deficits of the illness and the severity of these symptoms and deficits have in turn been associated with the magnitude of cortical gray matter reduction. Taken together, understanding the molecular underpinnings of pyramidal cell dysfunction will shed important light onto the pathophysiology of cortical dysfunction of schizophrenia. In order to gain insight into the molecular determinants of pyramidal cell dysfunction in schizophrenia, we combined LCM with Affymetrix microarray and high-throughput TaqManM-BM-.-based MegaPlex qRT-PCR approaches, respectively, to elucidate the alterations in messenger ribonucleic acid (mRNA) and microRNA (miRNA) expression profiles of these neurons in layer 3 of the STG. We found that transforming growth factor beta (TGFM-NM-2) and BMP (bone morphogenetic proteins) signaling pathways and many genes that regulate extracellular matrix (ECM), apoptosis and cytoskeleton were dysregulated in schizophrenia. In addition, we identified 10 miRNAs that were differentially expressed in this illness; interestingly, the predicted targets of these miRNAs included the dysregulated pathways and gene networks identified by microarray analysis. Together these findings provide a neurobiological framework within which we can begin to formulate and test specific hypotheses about the molecular mechanisms that underlie pyramidal cell dysfunction in schizophrenia. Gene epxression microarray from RNA isolated from pyramidal cells in layer III of the STG from 9 normal controls and 9 subjects with schizophrenia. There was no significant difference between diagnosis groups for age, sex, and post mortem interval (PMI).

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Cell type specific transcriptomic alterations in prefrontal deep-layer pyramidal neurons in individuals with a history of childhood abuse

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