Molecular signatures associated with cognitive deficits in schizophrenia: a study of biopsied olfactory neural epithelium

Abstract

Cognitive impairment is a key feature of schizophrenia (SZ) and determines functional outcome. Nonetheless, molecular signatures in neuronal tissues that associate with deficits are not well understood. We conducted nasal biopsy to obtain olfactory epithelium from patients with SZ and control subjects. The neural layers from the biopsied epithelium were enriched by laser-captured microdissection. We then performed an unbiased microarray expression study and implemented a systematic neuropsychological assessment on the same participants. The differentially regulated genes in SZ were further filtered based on correlation with neuropsychological traits. This strategy identified the SMAD 5 gene, and real-time quantitative PCR analysis also supports downregulation of the SMAD pathway in SZ. The SMAD pathway has been important in multiple tissues, including the role for neurodevelopment and bone formation. Here the involvement of the pathway in adult brain function is suggested. This exploratory study establishes a strategy to better identify neuronal molecular signatures that are potentially associated with mental illness and cognitive deficits. We propose that the SMAD pathway may be a novel target in addressing cognitive deficit of SZ in future studies.

Figure 1

Study design. Microarray analysis using olfactory epithelium (OE) tissue and neuropsychological assessments were conducted in the same participants. Following differential gene expression analysis (false discovery rate (FDR) <0.05), correlation of gene expression with neuropsychological test scores was used as a filter to select candidate genes for validation with quantitative real-time PCR (qPCR). To determine whether genes identified using OE would also be significantly different in lymphoblasts (LBs), we conducted microarray differential gene expression analysis in 'paired' and 'non-paired' samples.

Figure 2

Gene expression level of SMAD pathway-related genes in the olfactory epithelium (OE) neuronal layer. The mRNA expression level of SMAD pathway-related genes using quantitative real-time polymerase chain reaction (qPCR). The qPCR analysis confirmed downregulation of SMAD1, SMAD3 and SMAD5 in schizophrenia (SZ). Expression levels were normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Results are shown as mean±s.e.m. Statistical analysis was conducted with Welch's t-test. *P<0.05.