Gene expression differences in bipolar disorder revealed by cDNA array analysis of post‐mortem frontal cortex

Abstract

Previous studies have implicated a number of biochemical pathways in the etiology of bipolar disorder (BD). However, the precise abnormalities underlying this disorder remain to be established. To investigate novel factors that may be important in the pathophysiology of BD, we utilized cDNA expression arrays to examine differences in expression of up to 1200 genes known to be involved in potentially relevant biochemical processes. This investigation was undertaken in post-mortem samples of frontal cortex tissue from patients with BD and matched controls, obtained (n 10/group) from the Stanley Foundation Neuropathology Consortium. Results include signi®cant (greater than 35% change in signal intensity) differences between BD and controls in a number of genes (n 24). Selected targets were analyzed by RT-PCR, which con®rmed a decrease in transforming growth factor-beta1 (TGF-b1), and an increase in both caspase-8 precursor (casp-8) and transducer of erbB2 (Tob) expression in BD. We further observed a signi®cant decrease of TGF-b1 mRNA levels in BD by RT-PCR in individual post-mortem samples. Given the neuroprotective role attributed to this inhibitory cytokine, our results suggest that the downregulation of TGF-b1 may lead to various neurotoxic insults potentially involved in the etiology of certain mood disorders. Bipolar disorder (BD) is a common psychiatric illness, with a lifetime prevalence of approximately 1.5% (Goodwin and Jamison 1990;Goodwin and Ghaemi 1998). It is characterized by episodes of mania and depression exhibiting increasing chronicity and severity over time, and requires aggressive long-term prophylactic pharmacotherapy. While the causes of BD remain to be conclusively established, Post and colleagues have suggested that lasting neurobiological changes may arise as a result of episode-speci®c alterations in gene expression patterns (Post 1992;Post and Weiss 1996). More recently, studies have shown that changes in gene expression are critical to the effects of long-term treatment with mood stabilizing drugs (Hyman and Nestler 1996), and the associated biochemical mechanisms may be integral to the pathophysiology of BD.Signal transduction pathways are uniquely positioned for the transmission of extracellular signals to long-term neuroplastic events, given their central role in mediating diverse neurotransmitter functions and integrating neuronal communication in the CNS. A large number of reports have been published suggesting the involvement of signal transduction processes in the pathophysiology of BD, as well as in the action of mood stabilizing drugs (Mork et al. 1992; Lenox 1994, 2000a,b;Wang et al. 1997). Moreover, kindling and apoptosis have also provided useful models for understanding the long-term changes that may be associated with the disorder (Post and Weiss 1989; Post 1992), leading to investigation of these processes in BD. Of relevance, mood stabilizers can provide protection against cell death possibly through regulation of antiapoptotic genes (Nonaka et al. 1998), sugges...

Expression profiling in monozygotic twins discordant for bipolar disorder reveals dysregulation of the WNT signalling pathway

“…Previous microarray studies using post-mortem brains from BD1 patients have found differential expression of genes related to apoptosis and neuroprotection; 35,36 neurotransmission and energy metabolism; 37 mitochondrial function; 37,38 receptor/transport, stress response, molecular chaperones and transcription factors; 33 signal transduction; 33,35 myelination and oligodendrocyte function 39 and ubiquitin cycle and synaptic-related genes. 40 Microarray studies assessing white blood cell-derived gene expression levels in BD1 have found, among many different processes, aberrations in RNA binding and ribosomal function, 6 as well as the ER stress response.…”

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

“…Microarray work has revealed decreases in metabolic-associated transcripts in bipolar disorder. 91,92 However, decreased metabolic-associated transcripts have been associated with decreased brain pH, 34 a common confounding factor in psychiatric postmortem brain research. Due to this latter finding, it is important to interpret with care the data that is obtained from the Stanley array data set, which is not corrected for brain pH, as the mean values in the schizophrenia and bipolar groups are lower than in the control subjects.…”

Mitochondrial involvement in psychiatric disorders

“…Some microarray studies have not reported a broad mitochondrial gene expression pattern in BPD (72,73) or SZ (62,74,75). A few microarray studies in MDD have not reported that mitochondrial genes were differentially expressed in cortex (76)(77)(78).…”