Altered fatty acid concentrations in prefrontal cortex of schizophrenic patients

Abstract

Background

Disturbances in prefrontal cortex phospholipid and fatty acid composition have been reported in patients with schizophrenia (SCZ), often as an incomplete lipid profile or a percent of total lipid concentration. In this study, we quantified absolute concentrations (nmol/g wet weight) and fractional concentrations (i.e. percent of total fatty acids) of several lipid classes and their constituent fatty acids in postmortem prefrontal cortex of SCZ patients (n = 10) and age-matched controls (n = 10).

Methods

Lipids were extracted, fractionated with thin layer chromatography and assayed.

Results

Mean total lipid, phospholipid, individual phospholipids, plasmalogen, triglyceride and cholesteryl ester concentrations did not differ significantly between the groups. Compared to controls, SCZ brains showed significant increases in several monounsaturated and polyunsaturated fatty acid absolute concentrations in cholesteryl ester. Significant increases or decreases occurred in palmitoleic, linoleic, γ-linolenic and n-3 docosapentaenoic acid absolute concentrations in total lipids, triglycerides or phospholipids. Changes in fractional concentrations did not consistently reflect absolute concentration changes.

Conclusion

These findings suggest disturbed prefrontal cortex fatty acid absolute concentrations, particularly within cholesteryl esters, as a pathological aspect of schizophrenia.

Introduction

Schizophrenia (SCZ) is a mental disorder characterized by distortions in the perception of reality (Ross et al., 2006), which manifest as psychotic episodes involving hallucinations, delusions and/or thought disorder (Wong and Van Tol, 2003). SCZ affects approximately 0.5–1.0% of the world's population, and is associated with cognitive impairment, diminished emotional expression and poor quality of life (Ross et al., 2006).

The pathological causes of SCZ are not agreed upon, although one proposed contributing factor is disturbed brain lipid metabolism (Horrobin et al., 1994). In support of this suggestion, P-31 magnetic resonance spectroscopy (MRS) studies reported an increase in choline glycerophospholipid (ChoGpl) and phosphatidylinositol (PtdIns) concentrations, as well as increased phosphomonoester or phosphodiester products of phospholipid synthesis/breakdown in postmortem frontal cortex of SCZ patients relative to controls (Deicken et al., 1994; Komoroski et al., 2001, 2008; Miller et al., 2012; Pettegrew et al., 1991; Stanley et al., 1994; Williamson et al., 1991). These changes were not confirmed by a later study, however (Pearce et al., 2009). Thalamic concentrations of sphingomyelin and phosphatidylcholine were reported decreased, and of phosphatidylserine (PtdSer) increased in SCZ patients (Schmitt et al., 2004). Minimal or no changes in absolute phospholipid concentrations were reported in hippocampus (Hamazaki et al., 2010), caudate region (Yao et al., 2000), amygdala (Hamazaki et al., 2012) or cingulate gyrus (Landen et al., 2002), suggesting region-specific changes in brain phospholipid metabolism.

An increase in frontal cortex but not hippocampus membrane fluidity was reported in SCZ patients, also suggesting region-specific changes in membrane lipid composition and possibly in enzymes that regulate fatty acid turnover within membrane phospholipids (Eckert et al., 2011). In agreement with this suggestion, fractional concentrations (i.e. percent of total fatty acids) of the main brain polyunsaturated fatty acids (PUFAs), arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), were reported to be reduced (McNamara et al., 2007) or unchanged (Horrobin et al., 1991) in prefrontal cortex total lipids of SCZ patients. AA-containing ChoGpl absolute concentration, DHA fractional concentration in phosphatidylinositol (PtdIns) and docosapentaenoic acid (n-6 DPA, 22:5n-6) fractional concentration in PtdSer and PtdIns were increased in prefrontal cortex of SCZ patients compared to controls (Horrobin et al., 1991; Matsumoto et al., 2011), suggesting phospholipid-specific changes in fatty acid composition. An increase in postmortem frontal cortex activity of DHA-releasing calcium-independent phospholipase A₂ (iPLA₂)-VIA, and a decrease in temporal/frontal cortex and caudate putamen activity of AA-releasing calcium-dependent phospholipase cPLA₂-IVA was reported in SCZ patients (Ross et al., 1999), supporting the reported changes in AA and DHA composition and membrane fluidity (Eckert et al., 2011; Horrobin et al., 1991; McNamara et al., 2007; Yao et al., 2000). Minimal changes in fatty acid concentrations were reported in other brain regions, including hippocampus (Hamazaki et al., 2010), amygdala (Hamazaki et al., 2012), cingulate gyrus (Landen et al., 2002) or the caudate region, in which AA and linoleic acid (18:2n-6) fractional concentrations were reduced (Yao et al., 2000).

The cholesteryl ester pool is also affected in SCZ. Horrobin et al. reported a 43% decrease in the cholesteryl ester pool, and a 46–86% decrease in AA, DHA and linoleic acid absolute concentrations within cholesteryl esters, in frontal cortex of SCZ patients compared to controls (Horrobin et al., 1991). Cholesteryl ester is a precursor to free cholesterol and cholesterol oxidation products that were reported to increase after kainate-induced excitotoxicity (Kim et al., 2010; Ong et al., 2010). Cholesterol oxidation products were reported to facilitate kainate-induced neurotransmitter release by increasing intracellular calcium concentrations, and to induce apoptosis by inducing the pro-inflammatory NF-kappa-B and protein kinase B (Akt) transcription pathway in rat pheochromocytoma-12 cells (Jang and Lee, 2011; Ma et al., 2010).

In many of the postmortem studies, the reported lipid profile was incomplete, or fatty acid concentrations were expressed as fractional concentrations (i.e. percentage of total fatty acids) rather than per gram tissue wet weight, protein or phosphorous. Changes in fatty acid concentrations may not be accurately reflected by using fractional concentrations, particularly if the respective total lipid pool is altered (Taha and McIntyre Burnham, 2007), as has been reported in the phospholipid pool of SCZ patients (Deicken et al., 1994; Komoroski et al., 2001, 2008; Miller et al., 2012; Pettegrew et al., 1991; Williamson et al., 1991). Also, a change in one fatty acid reflects in the opposite direction in another, thereby limiting data interpretation and comparison between studies.

To comprehensively test the hypothesis that schizophrenia is associated with disturbed brain lipid metabolism, we quantified lipid concentrations, per gram brain wet weight, in postmortem prefrontal cortex (Brodmann area 10) of control and SCZ patients. We chose prefrontal cortex because of reported disturbances in lipid composition, membrane fluidity and PLA₂ activity in this region (Deicken et al., 1994; Horrobin et al., 1991; Komoroski et al., 2001, 2008; Matsumoto et al., 2011; McNamara et al., 2007; Pettegrew et al., 1991; Williamson et al., 1991; Yao et al., 2000), and because we wanted to compare our results to those on postmortem prefrontal cortex from bipolar disorder and Alzheimer's disease patients, to determine whether changes in lipid concentration were specific to one disease over the other (Igarashi et al., 2010, 2011). We also expressed our data as fractional concentrations (percent of total fatty acids) to compare our findings with other studies that reported fractional fatty acid concentrations in prefrontal cortex (Horrobin et al., 1991; McNamara et al., 2007).