Molecular Psychiatry (2006) 11, 547–556 & 2006 Nature Publishing Group All rights reserved 1359-4184/06 $30.00 www.nature.com/mp FEATURE REVIEW The role of phospholipases A2 in schizophrenia MH Law1, RGH Cotton1 and GE Berger1,2 1Genomic Disorders Research Centre, Melbourne, VI, Australia and 2ORYGEN Research Centre, Melbourne, VI, Australia A range of neurotransmitter systems have been implicated in the pathogenesis of schizophrenia based on the antidopaminergic activities of antipsychotic medications, and chemicals that can induce psychotic-like symptoms, such as ketamine or PCP. Such neurotransmitter systems often mediate their cellular response via G-protein-coupled release of arachidonic acid (AA) via the activation of phospholipases A2 (PLA2s). The interaction of three PLA2s are important for the regulation of the release of AA – phospholipase A2 Group 2 A, phospholipase A2 Group 4A and phospholipase A2 Group 6A. Gene variations of these three key enzymes have been associated with schizophrenia with conflicting results. Preclinical data suggest that the activity of these three enzymes are associated with monoaminergic neurotransmission, and may contribute to the differential efficacy of antipsychotic medications, as well as other biological changes thought to underlie schizophrenia, such as altered neurodevelopment and synaptic remodelling. We review the evidence and discuss the potential roles of these three key enzymes for schizophrenia with particular emphasis on published association studies. Molecular Psychiatry (2006) 11, 547–556. doi:10.1038/sj.mp.4001819; published online 4 April 2006 Keywords: review; schizophrenia/genetics; PLA2/genetics; arachidonic acid; common diseases; PLA2/schizophrenia Introduction (PLA2GVIA, PLA2G6A), dopamine, serotonin, G- protein-coupled receptor, eicosanoids and phospho- Neurotransmitters, such as dopamine, serotonin and lipids. Crosschecking of references was used to glutamate often mediate their cellular response via identify further papers of interest. G-protein-coupled activation of second messengers. One such common second messenger is arachidonic acid (AA) that is released from membrane phospho- PLA2s – naming conventions lipids via the G-protein-coupled activation of phos- pholipase A2 (PLA2).1 Phospholipase A2 activity and When analysing PLA2 studies it is essential to AA-based signalling is also important for normal properly define which enzymes are being examined. brain development and synaptic functioning.2–5 This Phospholipases A2 are a large family of enzymes that review outlines how PLA2s, in particular PLA2G2A, specifically deacylate fatty acids from the sterospeci- PLA2G4A and PLA2G6A, may be relevant for the fically numbered second carbon atom (sn2, thus understanding of schizophrenia pathogenesis and its PLA2) of the triglyceride backbone of membrane treatments.6 phospholipids, producing a free fatty acid and a lyso-phospholipid (Figure 1).7 Historically, PLA2s were named by activity location, that is pancreatic, Method cytosolic or secretory. Later naming systems also included calcium requirements, although this can be Medline and Google Scholar (www.scholar.google.- misleading. Some calcium-dependent PLA2s require com) were used to identify articles from 1970 to 2005 calcium for catalytic activity, whereas others are using the following key words: schizophrenia, essen- constitutively active and calcium promotes binding tial fatty acids (EFA), polyunsaturated fatty acid to phospholipid membranes. The more structured (PUFA), AA, PLA2, phospholipase A2 Group 4A classification system based on genetic relationships (PLA2GIVA, PLA2G4A), phospholipase A2 Group 2A will be used in this review.7 In this system each PLA2 (PLA2GIIA, PLA2G2A), phospholipase A2 Group 6A is assigned to one of (currently) 11 groups; each group may contain multiple homologues further assigned a Correspondence: Dr G Berger, ORYGEN Research Centre/ORYGEN letter. For example, phospholipase A2 Group 4A Youth Health, 35 Poplar rd, Parkville, Victoria 3052, Australia. E-mail: [email protected] (PLA2G4A) and phospholipase A2 Group 4B Received 14 December 2005; accepted 30 January 2006; published (PLA2G4B) are evolutionarily related homologues (A online 4 April 2006 and B) within Group 4 (G4). PLA2s and schizophrenia MH Law et al 548 Figure 1 De-acylation of arachidonic acid (AA) from a phospholipid by the activity of a PLA2 enzyme. Figure 2 Arachidonic acid release in response to receptor activation. (a) Initial or early stage AA release requires PLA2s and AA recruitment of PLA2G4A. (b) To promote and maintain AA release PLA2GA recruits PLA2G2A. PLA2s regulate both the availability of free lysopho- spholipids for AA membrane incorporation, and the cleavage of AA from membranes for signalling 8,9 G2A, PLA2G4A and PLA2G6A in both brain matura- (Figures 1 and 2). The polyunsaturated fatty acid tional processes and neurotransmission. (PUFA) AA itself is a potent signalling molecule, and also the precursor for a range of messengers (eicosa- 10,11 Neurotransmission noids) necessary for normal neuronal function. To The receptors for neurotransmitter systems impli- limit aberrant signalling AA is usually bound to cell cated in schizophrenia activate downstream re- membranes phospholipids. In addition to creating a sponses via a family of guanosine triphosphate reservoir for later release of AA in response to binding proteins (G-proteins), which in turn appropriate signals, the ratio of saturated to unsatu- activates PLA2G4A-mediated release of AA 26,27 rated fatty acids (such as AA) also defines membrane and recruit PLA2G2A to further enhance signalling fluidity, which alters the activity of membrane bound 5,11,17,28 12,13 (Figure 2). The colocalisation of monoaminer- proteins including neurotransmitter receptors. gic receptors with PLA2G4A, PLA2G2A and eicosa- PLA2G4A has a 50-fold preference for phospholi- noid-synthesising enzymes further emphasise their pids containing AA over any other PUFA, whereas importance for monoaminergic neurotransmis- PLA2G6A and PLA2G2A show no fatty acid pre- 15,29–31 14 sion. The proper functioning and availability ference. PLA2G4A initiates AA release and eicosa- of these PLA2s are therefore crucial for G-protein- noid production, whereas PLA2G2A enhances the coupled neurotransmission. production of AA (Figure 2).15–18 Mice with the genes for PLA2G4A and PLA2G2A nullified (knocked out) Memory formation (long-term potentiation) do not produce eicosanoids, have reduced incorpora- Long-term potentiation (LTP), the proposed mechan- tion rates of free AA into cell membranes, yet normal 19,20 ism for memory formation, is associated with AA levels. G-protein-coupled glutamate receptor (AMPAR) acti- PLA2G6A cleavage of phospholipids is primarily vation and release of AA.32–35 PLA2 inhibitors block for the purpose of cellular membrane remodelling, by AMPAR-associated LTP, while increasing PLA2 activ- altering phospholipids/fatty acid ratios and modify- 34 21,22 ity enhances LTP. PLA2 enhancement of LTP is ing membrane fluidity. Loss of PLA2G6A function halted by sequestering free AA, but not by removing leads to significant reductions in the amount of AA 34,36 23 calcium or blocking eicosanoid production. Gen- incorporated into the cell membrane. eral inhibition of brain PLA2 activity, and particularly specific inhibition of PLA2G6A activity decreased PLA2 in neurobiology memory formation in rats and reduced membrane fluidity, revealing the requirement of PLA2G6A in The neurodevelopmental hypothesis and the neuro- memory formation.37 transmitter theories of schizophrenia propose that abnormal genetic and environmental processes inter- Brain maturation, cortical development and synaptic fere with normal brain maturation and result in remodelling dysfunctional monoaminergic neurotransmission as- Brain maturation, cortical development and synaptic sociated with the phenotype of schizophrenia.24,25 remodelling involves removal of excess brain cells or The following evidence outlines the roles of PLA2- parts of cells such as dendrites or axons. Key regulator Molecular Psychiatry PLA2s and schizophrenia MH Law et al 549 proteins involved in these processes are the caspases, tion between peripheral AA levels and brain phos- in particular caspase 3. Caspases manage apoptotic pholipid metabolism. cellular metabolism via the cleavage of certain proteins such as PLA2G4A and PLA2G6A into Niacin insensitivity – a marker for an abnormal AA alternative forms, altering their behaviour.22 Cleaved metabolism PLA2G4A proteins have a dominant-negative func- The vitamin nicotinic acid (niacin) induces the tion, halting cellular PLA2G4A activity. Truncation of release of inflammatory eicosanoids such as prosta- PLA2G6A upregulates its activity, allowing rapid glandin D2, which are produced from AA metabo- remodelling of the cellular membrane and generation lism.60 Depending on the method/definitions used, of free AA required for apoptosis.38 The remodelled 40–80% of patients with psychotic disorders and membranes generates phagocytic attraction signals to 10% of controls show an impaired sensitivity to allow correct disposal of the cell remnants created niacin.61–64 Niacin sensitivity is also impaired in resulting from the apoptotic process.22,39–41 healthy first degree relatives of probands, suggesting While not required within apoptotic neurons, it is a marker for underlying genetic risk.65 Niacin complete loss of PLA2G4A and PLA2G2A abolishes insensitivity remains associated with schizophrenia