Key role for lipids in cognitive symptoms of schizophrenia

Abstract

Schizophrenia (SZ) is a psychiatric disorder with a convoluted etiology that includes cognitive symptoms, which arise from among others a dysfunctional dorsolateral prefrontal cortex (dlPFC). In our search for the molecular underpinnings of the cognitive deficits in SZ, we here performed RNA sequencing of gray matter from the dlPFC of SZ patients and controls. We found that the differentially expressed RNAs were enriched for mRNAs involved in the Liver X Receptor/Retinoid X Receptor (LXR/RXR) lipid metabolism pathway. Components of the LXR/RXR pathway were upregulated in gray matter but not in white matter of SZ dlPFC. Intriguingly, an analysis for shared genetic etiology, using two SZ genome-wide association studies (GWASs) and GWAS data for 514 metabolites, revealed genetic overlap between SZ and acylcarnitines, VLDL lipids, and fatty acid metabolites, which are all linked to the LXR/RXR signaling pathway. Furthermore, analysis of structural T₁-weighted magnetic resonance imaging in combination with cognitive behavioral data showed that the lipid content of dlPFC gray matter is lower in SZ patients than in controls and correlates with a tendency towards reduced accuracy in the dlPFC-dependent task-switching test. We conclude that aberrations in LXR/RXR-regulated lipid metabolism lead to a decreased lipid content in SZ dlPFC that correlates with reduced cognitive performance.

Fig. 1. Expression of LXR/RXR-related mRNAs in SZ vs. control dlPFC gray and white matter.

a Normalized mRNA expression of angiotensinogen (Agt), apolipoprotein C2 (Apoc2), and complement 4b (C4b) in SZ vs. control dlPFC gray matter. These mRNAs are components of the canonical pathway “LXR/RXR activation” in the Ingenuity pathway analysis. b Normalized mRNA expression of the LXR/RXR signaling cascade components Liver X receptor β (Lxrβ), retinoid X receptor β (Rxrβ), ATP-binding cassette transporter A1 (Abca1), peripheral myelin protein 22 (Pmp22), apolipoprotein E (ApoE), and sterol regulatory element-binding protein 1 (SREBP1) in SZ vs. control dlPFC gray matter. c, d Normalized mRNA expression of the same genes as in a and b in the white matter of dlPFC. n = 4 samples per group, #p < 0.1, *p < 0.05 in independent samples T-test.

Fig. 2. MP-RAGE signal in SZ and control dlPFC gray matter and correlation with task-switching accuracy.

a Left: schematic representation of the dlPFC gray matter in the left and right brain hemispheres. Right: average MP-RAGE signal from the left and right dlPFC gray matter in SZ versus control (CON). **p < 0.001 in a linear model corrected for sex, age, motion, and scanning site. b Scatter plot of the accuracy in the task-switching test and the MP-RAGE signal from the dlPFC gray matter in the left and right hemisphere of SZ patients.

Fig. 3. Molecular pathways involving LXR/RXR signaling, acylcarnitines, VLDL lipids, and fatty acid metabolites.

Dark green rectangles represent genes upregulated in SZ dlPFC. Light green ovals represent lipid-related metabolites that share significant genetic etiology with SZ. Arrows indicate the nature of molecular interactions (see legend in the figure for details). References^,,– have been used to construct the molecular pathways.