Abstract
Disrupted synchronized oscillatory firing of pyramidal neuronal networks in the cerebral cortex in the gamma frequency band (i.e., 30–100 Hz) mediates many of the cognitive deficits and symptoms of schizophrenia. In fact, the density of dendritic spines and the average somal area of pyramidal neurons in layer 3 of the cerebral cortex, which mediate both long-range (associational) and local (intrinsic) corticocortical connections, are decreased in subjects with this illness. To explore the molecular pathophysiology of pyramidal neuronal dysfunction, we extracted ribonucleic acid (RNA) from laser-captured pyramidal neurons from layer 3 of Brodmann's area 42 of the superior temporal gyrus (STG) from postmortem brains from schizophrenia and normal control subjects. We then profiled the messenger RNA (mRNA) expression of these neurons, using microarray technology. We identified 1331 mRNAs that were differentially expressed in schizophrenia, including genes that belong to the transforming growth factor beta (TGF-β) and the bone morphogenetic proteins (BMPs) signaling pathways. Disturbances of these signaling mechanisms may in part contribute to the altered expression of other genes found to be differentially expressed in this study, such as those that regulate extracellular matrix (ECM), apoptosis, and cytoskeletal and synaptic plasticity. In addition, we identified 10 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of their predicted gene targets revealed signaling pathways and gene networks that were found by microarray to be dysregulated, raising an interesting possibility that dysfunction of pyramidal neurons in schizophrenia may in part be mediated by a concerted dysregulation of gene network functions as a result of the altered expression of a relatively small number of miRNAs. Taken together, findings of this study provide a neurobiological framework within which specific hypotheses about the molecular mechanisms of pyramidal cell dysfunction in schizophrenia can be formulated.
Highlights
Gray matter volume in the cerebral cortex has been consistently found to be decreased in patients with schizophrenia (Ananth et al, 2002; Wilke et al, 2001)
We found that transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) signaling pathways and many genes that regulate extracellular matrix (ECM), apoptosis and cytoskeleton were dysregulated in schizophrenia
We evaluated the reliability of our findings by assessing messenger RNA (mRNA) quality based on a combination of metrics, as there is not a single parameter that can serve as the sole determinant or predictor of mRNA quality
Summary
Gray matter volume in the cerebral cortex has been consistently found to be decreased in patients with schizophrenia (Ananth et al, 2002; Wilke et al, 2001). Synchronized activities of pyramidal neuronal networks through these connections, especially in the gamma frequency band (i.e., 30–100 Hz), are critical for the integrity of higher cortical functions (Buzsaki & Draguhn, 2004) Disturbances of these networks may contribute to the pathophysiology of schizophrenia by compromising gamma oscillation (Arnsten et al, 2010; Lewis & Gonzalez-Burgos, 2008; Uhlhaas & Singer, 2010). The density of dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex, including the STG, have been shown to be decreased by 23–66% in subjects with schizophrenia (Costa et al, 2001; Garey et al, 1998; Glantz & Lewis, 2000; Sweet et al, 2009) Consistent with these findings, the average somal area of these pyramidal cells is significantly smaller (Sweet et al, 2003, 2004). Taken together, understanding the molecular underpinnings of pyramidal cell functional impairment will shed important light onto the pathophysiology and thereby the conceptualization of novel and rational treatment of cortical dysfunction in schizophrenia
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