- Email: [email protected]
Dysfunctional glycosynapses in schizophrenia: Disease and regional specificity
Schizophrenia Research 166 (2015) 235–237
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Dysfunctional glycosynapses in schizophrenia: Disease and regional specificity Paul L. Wood ⁎, Nicole R. Holderman Metabolomics Unit, Dept. of Physiology and Pharmacology, DeBusk College of Osteopathic Medicine, Lincoln Memorial University, 6965 Cumberland Gap Pkwy., Harrogate, TN 37752, United States
a r t i c l e
i n f o
Article history: Received 18 March 2015 Received in revised form 4 May 2015 Accepted 7 May 2015 Available online 23 May 2015 Keywords: Schizophrenia Glycosynapse Sulfatides Dysconnectivity Plasmalogens N-acylphosphatidylserines Frontal cortex Cerebellum
a b s t r a c t Background: Our previous lipidomics studies demonstrated elevated sulfatides, plasmalogens, and N-acylphosphatidylserines in the frontal cortex of schizophrenia subjects. These data suggest that there may be an abnormal function of glycosynapses in schizophrenia. We further examined the disease and anatomical specificity of these observations. Methods: We undertook a targeted lipidomics analysis of plasmalogens, sulfatides, and N-acyl-phosphatidylserines in the frontal cortex obtained from schizophrenia, bipolar, and ALS subjects and the cerebellum of schizophrenia subjects. Results: We demonstrate that sulfatides, plasmalogens, and N-acyl-phosphatidylserines are significantly elevated in the frontal cortex of patients suffering from schizophrenia and bipolar depression but not in ALS patients. These lipids were unchanged in the cerebellum of subjects with schizophrenia. Conclusions: Our data suggest that dysfunction of oligodendrocyte glycosynapses may be specific to limbic circuits in schizophrenia and that this dysfunction is also detected in bipolar depression, suggesting that these disorders possess several common pathophysiological features. © 2015 Elsevier B.V. All rights reserved.
1. Introduction
2. Materials and methods
Both anatomical and imaging studies have suggested that schizophrenia is characterized by anatomical and functional dysconnectivity (Nakamura et al., 2005; Uranova et al., 2011). Non-targeted lipidomics studies have demonstrated elevated sulfatides (Wood et al., 2014a), plasmalogens (Wood et al., 2014a), and N-acylphosphatidylserines (Wood, 2014) in the frontal cortex of schizophrenia subjects. These lipids are essential for glycosynapse function, which includes both metabolic and trophic support to axons. These lipidomics findings suggest that dysfunctional oligodendrocyte glycosynapses (Boggs, 2014) may represent an important defect in the etiology of schizophrenia. We undertook a study to further evaluate the disease and anatomical specificity of these structural lipid changes. For disease specificity, we evaluated the frontal cortex from subjects with schizophrenia (SZ), bipolar disorder (BD), and amyotrophic lateral sclerosis (ALS). For anatomical specificity we compared the frontal cortex and cerebellar cortex from subjects with SZ.
2.1. Patient brain samples Frontal cortex brain (BA 9) samples included 10 controls, 10 schizophrenia, 10 bipolar disorder, and 10 ALS and were provided by the UCLA brain bank. Cerebellar cortex samples included 10 controls and 10 schizophrenia subjects were provided by the UCLA brain bank. Patients were diagnosed based on the Structural Interview for Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV). The demographics of the donors are presented in Table 1. 2.2. High resolution mass spectrometry Tissue samples were processed as described previously (Wood and Shirley, 2013; Wood et al., 2014a,b; Wood et al., 2015). Targeted lipidomics were performed utilizing high-resolution (140,000 at 200 amu) data acquisition on an orbitrap mass spectrometer (Thermo Q Exactive) with 0.2 to 3 ppm mass error. 2.3. Data analyses
⁎ Corresponding author. E-mail address: [email protected] (P.L. Wood).
http://dx.doi.org/10.1016/j.schres.2015.05.017 0920-9964/© 2015 Elsevier B.V. All rights reserved.
Data are presented as R values (ratio of the endogenous lipid to the peak area of an appropriate internal standard), corrected for tissue wet
236
P.L. Wood, N.R. Holderman / Schizophrenia Research 166 (2015) 235–237
Table 1 Demographics of the donors for the frontal cortex and cerebellar cortex samples. The group values are means ± SD and (ranges). Diagnosis
Age
Gender
PMI (Hr.)
Controls
71.1 ± 16.5 (35–92) 61.8 ± 17.0 (33–85) 60.1 ± 16.2 (35–94) 66.2 ± 18.7 (40–82)
6 M/4 F
16.2 ± 4.0 (9.3–23.7) 15.6 ± 5.3 (10.7–21.7) 16.3 ± 5.0 (9.7–21.3) 16.1 ± 4.0 (7.5–20.5)
Schizophrenia Bipolar ALS
4 M/6 F 3 M/7 F 5 M/5 F
weight, in bar graphs ± SEM. Data were analyzed with the Kruskal– Wallis test, followed by the Dunn's t test to compare clinical groups to the control group. 3. Results
Fig. 2. Levels of sulfatides, plasmalogens, and NAPS in postmortem cerebellar cortex obtained from controls (Con) and subjects suffering from schizophrenia (SZ) Y-axis is the ratio of the peak area of the endogenous lipid to the peak area of a stable isotope internal standard, corrected for tissue wet weight. Data are presented as mean ± SEM (N = 8–10).
3.1. Frontal cortex Sulfatides, choline plasmalogens, ethanolamine plasmalogens, and N-acyl-phosphatidylserines (NAPS) all were elevated in the frontal cortex of postmortem schizophrenia and bipolar tissue but not in ALS tissue (Fig. 1). There was no correlation of lipid changes with respect to gender or age, however, the data were obtained with an N of only 10 per group. These data differ with previous data demonstrating no alterations in frontal cortex plasmalogens in BPD (Igarashi et al., 2010). 3.2. Cerebellum No lipid differences were monitored in the cerebellar cortex between control and SZ subjects (Fig. 2). 4. Discussion We concluded previously (Wood et al., 2014a) that altered levels of sulfatides and plasmalogens in the frontal cortex of SZ subjects represent critical alterations in structural sphingolipids and glycerophospholipids that are responsible for dysfunctional myelin in SZ. Our new data are the first to demonstrate that these structural lipid alterations are common to SZ and to BD, supporting previous research that
has suggested that these disorders share a number of common pathophysiological features. Of relevance to our observed lipid alterations are the reports of altered extracellular matrix function in both SZ and BD. Increased expression of DNA-methyltransferase-1 in GABAergic interneurons in the frontal cortex of SZ and BD subjects results in decreased expression of glutamic acid decarboxylase (GAD67), brain-derived neurotrophic factor (BDNF), and extracellular matrix (ECM) proteoglycans like reelin and chondroitin sulfates (Berretta, 2012; Dong et al., 2014). The NCAN gene, which encodes a brain-specfic chondroitin sulfate, also is a risk factor for both SZ and BD (Schultz et al., 2014; Raum et al., 2015). The relationships between altered ECM function and structural myelin lipid changes still remains to be determined in SZ and BD. However, it appears that increased sulfatide expression results in augmented ECM proteolysis by matrix metalloproteinases (Yamamoto et al., 2014) and that lipid–protein interactions are essential for the transport and molecular organization of myelin proteins (Baron et al., 2014; Ozgen et al., 2014). Alterations in structural lipids and the ECM may also be responsible for dendritic spine loss (Dotti et al., 2014; Konopaske et al., 2014) and white matter glial pathology (Hercher et al., 2014) observed in the frontal cortex in SZ and BD. In toto, these multiple structural changes presumably are the result of polgenic risks that culminate in functional CNS deficits including cognitive impairment in SZ and BD (Barch and Sheffield, 2014) and abnormal GABAergic inhibitory neurotransmission in the frontal cortex in SZ (Radhu et al., 2015). Continued studies of the interrelationships of structural lipids with proteoglycans of the ECM (Raum et al., 2015) and oligodendrocyte synapses (Boggs, 2014) will be essential in gaining a more in-depth understanding of SZ and BD. In summary, these data demonstrate regional specificity of dysfunctional glycosynapses in schizophrenia and that this is a shared pathophysiologic feature with bipolar disorder. The limitations of the study are the potential confounds of chronic psychotropic drug use, smoking, and substance abuse in these patient populations. Evaluation of drug naïve subjects will be required to address this issue. Funding source The authors declare no competing financial interests. The funding sources also had no role in these studies.
Fig. 1. Levels of hydroxylated sulfatides, plasmalogens, and NAPS in gray matter (GM) of the postmortem frontal cortex obtained from subjects suffering from schizophrenia (SZ), bipolar disorder (BD), and amyotrophic lateral sclerosis (ALS). Y-axis is the ratio of the peak area of the endogenous lipid to the peak area of a stable isotope internal standard, corrected for tissue wet weight. Data are presented as mean ± SEM (N = 8–10); *, p b 0.05 vs. controls (Con).
Author contributions PLW and NRH contributed equally to the experimental design, conduct of experiments, data analysis, and writing of the manuscript. Competing financial interests The authors declare no competing financial interests. The funding sources also had no role in these studies.
P.L. Wood, N.R. Holderman / Schizophrenia Research 166 (2015) 235–237 Acknowledgments Frontal cortex and cerebellar cortex specimens were obtained from the Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Center, 11301 Wilshire Blvd. Los Angeles, CA 90073 which is sponsored by National Institutes of Health, National Multiple Sclerosis Society and the US Department of Veterans Affairs. This work was funded by DeBusk College of Osteopathic Medicine, Lincoln Memorial.
References Barch, D.M., Sheffield, J.M., 2014. Cognitive impairments in psychotic disorders: common mechanisms and measurement. World Psychiatry 13, 224–232. Baron, W., Bijlard, M., Nomden, A., de Jonge, J.C., Teunissen, C.E., Hoekstra, D., 2014. Sulfatide-mediated control of extracellular matrix-dependent oligodendrocyte maturation. Glia 62, 927–942. Berretta, S., 2012. Extracellular matrix abnormalities in schizophrenia. Neuropharmacology 62, 1584–1597. Boggs, J.M., 2014. Role of galactosylceramide and sulfatide in oligodendrocytes and CNS myelin: formation of a glycosynapse. Adv. Neurobiol. 9, 263–291. Dong, E., Ruzicka, W.B., Grayson, D.R., Guidotti, A., 2014. DNA-methyltransferase1 (DNMT1) binding to CpG rich GABAergic and BDNF promoters is increased in the brain of schizophrenia and bipolar disorder patients. Schizophr. Res. http://dx.doi.org/10. 1016/j.schres.2014.10.030. Dotti, C.G., Esteban, J.A., Ledesma, M.D., 2014. Lipid dynamics at dendritic spines. Front. Neuroanat. 8, 76. Hercher, C., Chopra, V., Beasley, C.L., 2014. Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder. J. Psychiatry Neurosci. 39, 376–385. Igarashi, M., Ma, K., Gao, F., Kim, H.W., Greenstein, D., Rapoport, S.I., Rao, J.S., 2010. Brain lipid concentrations in bipolar disorder. J. Psychiatr. Res. 44, 177–182. Konopaske, G.T., Lange, N., Coyle, J.T., Benes, F.M., 2014. Prefrontal cortical dendritic spine pathology in schizophrenia and bipolar disorder. JAMA Psychiatry 71, 1323–1331. Nakamura, M., McCarley, R.W., Kubicki, M., Dickey, C.C., Niznikiewicz, M.A., Voglmaier, M.M., Seidman, L.J., Maier, S.E., Westin, C.F., Kikinis, R., Shenton, M.E., 2005. Frontotemporal disconnectivity in schizotypal personality disorder: a diffusion tensor imaging study. Biol. Psychiatry 58, 468–478.
237
Ozgen, H., Schrimpf, W., Hendrix, J., de Jonge, J.C., Lamb, D.C., Hoekstra, D., Kahya, N., Baron, W., 2014. The lateral membrane organization and dynamics of myelin proteins PLP and MBP are dictated by distinct galactolipids and the extracellular matrix. PLoS One 9, e101834. Radhu, N., Garcia Dominguez, L., Farzan, F., Richter, M.A., Semeralul, M.O., Chen, R., Fitzgerald, P.B., Daskalakis, Z.J., 2015. Evidence for inhibitory deficits in the prefrontal cortex in schizophrenia. Brain 138, 483–497. Raum, H., Dietsche, B., Nagels, A., Witt, S.H., Rietschel, M., Kircher, T., Krug, A., 2015. A genome-wide supported psychiatric risk variant in NCAN influences brain function and cognitive performance in healthy subjects. Hum. Brain Mapp. 36, 378–390. Schultz, C.C., Mühleisen, T.W., Nenadic, I., Koch, K., Wagner, G., Schachtzabel, C., Siedek, F., Nöthen, M.M., Rietschel, M., Deufel, T., Kiehntopf, M., Cichon, S., Reichenbach, J.R., Sauer, H., Schlösser, R.G., 2014. Common variation in NCAN, a risk factor for bipolar disorder and schizophrenia, influences local cortical folding in schizophrenia. Psychol. Med. 44, 811–820. Uranova, N.A., Vikhreva, O.V., Rachmanova, V.I., Orlovskaya, D.D., 2011. Ultrastructural alterations of myelinated fibers and oligodendrocytes in the prefrontal cortex in schizophrenia: a postmortem morphometric study. Schizophr. Res. Treat. 2011, 325789. Wood, P.L., 2014. Accumulation of N-acylphosphatidylserines and N-acylserines in the frontal cortex in schizophrenia. Neurotransmitter 1, e263. Wood, P.L., Shirley, N.R., 2013. Lipidomics analysis of postmortem interval: preliminary evaluation of human skeletal muscle. Metabolomics 3, 3. Wood, P.L., Filiou, M.D., Otte, D.M., Zimmer, A., Turck, C.W., 2014a. Lipidomics reveals dysfunctional glycosynapses in schizophrenia and the G72/G30 transgenic mouse. Schizophr. Res. 159, 365–369. Wood, P.L., Phillipps, A., Woltjer, R.L., Kaye, J.A., Quinn, J.F., 2014b. Increased lysophosphatidylethanolamine and diacylglycerol levels in Alzheimer's disease plasma. JSM Alzheimer's Disease and Related Dementia 1, 1001. Wood, P.L., Unfried, G., Whitehead, W., Phillipps, A., Wood, J.A., 2015. Dysfunctional plasmalogen dynamics in the plasma and platelets of patients with schizophrenia. Schizophr. Res. 161, 506–510. Yamamoto, K., Miyazaki, K., Higashi, S., 2014. Pericellular proteolysis by matrix metalloproteinase-7 is differentially modulated by cholesterol sulfate, sulfatide, and cardiolipin. FEBS J. 281, 3346–3356.
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Dysfunctional glycosynapses in schizophrenia: Disease and regional specificity Paul L. Wood ⁎, Nicole R. Holderman Metabolomics Unit, Dept. of Physiology and Pharmacology, DeBusk College of Osteopathic Medicine, Lincoln Memorial University, 6965 Cumberland Gap Pkwy., Harrogate, TN 37752, United States
a r t i c l e
i n f o
Article history: Received 18 March 2015 Received in revised form 4 May 2015 Accepted 7 May 2015 Available online 23 May 2015 Keywords: Schizophrenia Glycosynapse Sulfatides Dysconnectivity Plasmalogens N-acylphosphatidylserines Frontal cortex Cerebellum
a b s t r a c t Background: Our previous lipidomics studies demonstrated elevated sulfatides, plasmalogens, and N-acylphosphatidylserines in the frontal cortex of schizophrenia subjects. These data suggest that there may be an abnormal function of glycosynapses in schizophrenia. We further examined the disease and anatomical specificity of these observations. Methods: We undertook a targeted lipidomics analysis of plasmalogens, sulfatides, and N-acyl-phosphatidylserines in the frontal cortex obtained from schizophrenia, bipolar, and ALS subjects and the cerebellum of schizophrenia subjects. Results: We demonstrate that sulfatides, plasmalogens, and N-acyl-phosphatidylserines are significantly elevated in the frontal cortex of patients suffering from schizophrenia and bipolar depression but not in ALS patients. These lipids were unchanged in the cerebellum of subjects with schizophrenia. Conclusions: Our data suggest that dysfunction of oligodendrocyte glycosynapses may be specific to limbic circuits in schizophrenia and that this dysfunction is also detected in bipolar depression, suggesting that these disorders possess several common pathophysiological features. © 2015 Elsevier B.V. All rights reserved.
1. Introduction
2. Materials and methods
Both anatomical and imaging studies have suggested that schizophrenia is characterized by anatomical and functional dysconnectivity (Nakamura et al., 2005; Uranova et al., 2011). Non-targeted lipidomics studies have demonstrated elevated sulfatides (Wood et al., 2014a), plasmalogens (Wood et al., 2014a), and N-acylphosphatidylserines (Wood, 2014) in the frontal cortex of schizophrenia subjects. These lipids are essential for glycosynapse function, which includes both metabolic and trophic support to axons. These lipidomics findings suggest that dysfunctional oligodendrocyte glycosynapses (Boggs, 2014) may represent an important defect in the etiology of schizophrenia. We undertook a study to further evaluate the disease and anatomical specificity of these structural lipid changes. For disease specificity, we evaluated the frontal cortex from subjects with schizophrenia (SZ), bipolar disorder (BD), and amyotrophic lateral sclerosis (ALS). For anatomical specificity we compared the frontal cortex and cerebellar cortex from subjects with SZ.
2.1. Patient brain samples Frontal cortex brain (BA 9) samples included 10 controls, 10 schizophrenia, 10 bipolar disorder, and 10 ALS and were provided by the UCLA brain bank. Cerebellar cortex samples included 10 controls and 10 schizophrenia subjects were provided by the UCLA brain bank. Patients were diagnosed based on the Structural Interview for Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV). The demographics of the donors are presented in Table 1. 2.2. High resolution mass spectrometry Tissue samples were processed as described previously (Wood and Shirley, 2013; Wood et al., 2014a,b; Wood et al., 2015). Targeted lipidomics were performed utilizing high-resolution (140,000 at 200 amu) data acquisition on an orbitrap mass spectrometer (Thermo Q Exactive) with 0.2 to 3 ppm mass error. 2.3. Data analyses
⁎ Corresponding author. E-mail address: [email protected] (P.L. Wood).
http://dx.doi.org/10.1016/j.schres.2015.05.017 0920-9964/© 2015 Elsevier B.V. All rights reserved.
Data are presented as R values (ratio of the endogenous lipid to the peak area of an appropriate internal standard), corrected for tissue wet
236
P.L. Wood, N.R. Holderman / Schizophrenia Research 166 (2015) 235–237
Table 1 Demographics of the donors for the frontal cortex and cerebellar cortex samples. The group values are means ± SD and (ranges). Diagnosis
Age
Gender
PMI (Hr.)
Controls
71.1 ± 16.5 (35–92) 61.8 ± 17.0 (33–85) 60.1 ± 16.2 (35–94) 66.2 ± 18.7 (40–82)
6 M/4 F
16.2 ± 4.0 (9.3–23.7) 15.6 ± 5.3 (10.7–21.7) 16.3 ± 5.0 (9.7–21.3) 16.1 ± 4.0 (7.5–20.5)
Schizophrenia Bipolar ALS
4 M/6 F 3 M/7 F 5 M/5 F
weight, in bar graphs ± SEM. Data were analyzed with the Kruskal– Wallis test, followed by the Dunn's t test to compare clinical groups to the control group. 3. Results
Fig. 2. Levels of sulfatides, plasmalogens, and NAPS in postmortem cerebellar cortex obtained from controls (Con) and subjects suffering from schizophrenia (SZ) Y-axis is the ratio of the peak area of the endogenous lipid to the peak area of a stable isotope internal standard, corrected for tissue wet weight. Data are presented as mean ± SEM (N = 8–10).
3.1. Frontal cortex Sulfatides, choline plasmalogens, ethanolamine plasmalogens, and N-acyl-phosphatidylserines (NAPS) all were elevated in the frontal cortex of postmortem schizophrenia and bipolar tissue but not in ALS tissue (Fig. 1). There was no correlation of lipid changes with respect to gender or age, however, the data were obtained with an N of only 10 per group. These data differ with previous data demonstrating no alterations in frontal cortex plasmalogens in BPD (Igarashi et al., 2010). 3.2. Cerebellum No lipid differences were monitored in the cerebellar cortex between control and SZ subjects (Fig. 2). 4. Discussion We concluded previously (Wood et al., 2014a) that altered levels of sulfatides and plasmalogens in the frontal cortex of SZ subjects represent critical alterations in structural sphingolipids and glycerophospholipids that are responsible for dysfunctional myelin in SZ. Our new data are the first to demonstrate that these structural lipid alterations are common to SZ and to BD, supporting previous research that
has suggested that these disorders share a number of common pathophysiological features. Of relevance to our observed lipid alterations are the reports of altered extracellular matrix function in both SZ and BD. Increased expression of DNA-methyltransferase-1 in GABAergic interneurons in the frontal cortex of SZ and BD subjects results in decreased expression of glutamic acid decarboxylase (GAD67), brain-derived neurotrophic factor (BDNF), and extracellular matrix (ECM) proteoglycans like reelin and chondroitin sulfates (Berretta, 2012; Dong et al., 2014). The NCAN gene, which encodes a brain-specfic chondroitin sulfate, also is a risk factor for both SZ and BD (Schultz et al., 2014; Raum et al., 2015). The relationships between altered ECM function and structural myelin lipid changes still remains to be determined in SZ and BD. However, it appears that increased sulfatide expression results in augmented ECM proteolysis by matrix metalloproteinases (Yamamoto et al., 2014) and that lipid–protein interactions are essential for the transport and molecular organization of myelin proteins (Baron et al., 2014; Ozgen et al., 2014). Alterations in structural lipids and the ECM may also be responsible for dendritic spine loss (Dotti et al., 2014; Konopaske et al., 2014) and white matter glial pathology (Hercher et al., 2014) observed in the frontal cortex in SZ and BD. In toto, these multiple structural changes presumably are the result of polgenic risks that culminate in functional CNS deficits including cognitive impairment in SZ and BD (Barch and Sheffield, 2014) and abnormal GABAergic inhibitory neurotransmission in the frontal cortex in SZ (Radhu et al., 2015). Continued studies of the interrelationships of structural lipids with proteoglycans of the ECM (Raum et al., 2015) and oligodendrocyte synapses (Boggs, 2014) will be essential in gaining a more in-depth understanding of SZ and BD. In summary, these data demonstrate regional specificity of dysfunctional glycosynapses in schizophrenia and that this is a shared pathophysiologic feature with bipolar disorder. The limitations of the study are the potential confounds of chronic psychotropic drug use, smoking, and substance abuse in these patient populations. Evaluation of drug naïve subjects will be required to address this issue. Funding source The authors declare no competing financial interests. The funding sources also had no role in these studies.
Fig. 1. Levels of hydroxylated sulfatides, plasmalogens, and NAPS in gray matter (GM) of the postmortem frontal cortex obtained from subjects suffering from schizophrenia (SZ), bipolar disorder (BD), and amyotrophic lateral sclerosis (ALS). Y-axis is the ratio of the peak area of the endogenous lipid to the peak area of a stable isotope internal standard, corrected for tissue wet weight. Data are presented as mean ± SEM (N = 8–10); *, p b 0.05 vs. controls (Con).
Author contributions PLW and NRH contributed equally to the experimental design, conduct of experiments, data analysis, and writing of the manuscript. Competing financial interests The authors declare no competing financial interests. The funding sources also had no role in these studies.
P.L. Wood, N.R. Holderman / Schizophrenia Research 166 (2015) 235–237 Acknowledgments Frontal cortex and cerebellar cortex specimens were obtained from the Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Center, 11301 Wilshire Blvd. Los Angeles, CA 90073 which is sponsored by National Institutes of Health, National Multiple Sclerosis Society and the US Department of Veterans Affairs. This work was funded by DeBusk College of Osteopathic Medicine, Lincoln Memorial.
References Barch, D.M., Sheffield, J.M., 2014. Cognitive impairments in psychotic disorders: common mechanisms and measurement. World Psychiatry 13, 224–232. Baron, W., Bijlard, M., Nomden, A., de Jonge, J.C., Teunissen, C.E., Hoekstra, D., 2014. Sulfatide-mediated control of extracellular matrix-dependent oligodendrocyte maturation. Glia 62, 927–942. Berretta, S., 2012. Extracellular matrix abnormalities in schizophrenia. Neuropharmacology 62, 1584–1597. Boggs, J.M., 2014. Role of galactosylceramide and sulfatide in oligodendrocytes and CNS myelin: formation of a glycosynapse. Adv. Neurobiol. 9, 263–291. Dong, E., Ruzicka, W.B., Grayson, D.R., Guidotti, A., 2014. DNA-methyltransferase1 (DNMT1) binding to CpG rich GABAergic and BDNF promoters is increased in the brain of schizophrenia and bipolar disorder patients. Schizophr. Res. http://dx.doi.org/10. 1016/j.schres.2014.10.030. Dotti, C.G., Esteban, J.A., Ledesma, M.D., 2014. Lipid dynamics at dendritic spines. Front. Neuroanat. 8, 76. Hercher, C., Chopra, V., Beasley, C.L., 2014. Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder. J. Psychiatry Neurosci. 39, 376–385. Igarashi, M., Ma, K., Gao, F., Kim, H.W., Greenstein, D., Rapoport, S.I., Rao, J.S., 2010. Brain lipid concentrations in bipolar disorder. J. Psychiatr. Res. 44, 177–182. Konopaske, G.T., Lange, N., Coyle, J.T., Benes, F.M., 2014. Prefrontal cortical dendritic spine pathology in schizophrenia and bipolar disorder. JAMA Psychiatry 71, 1323–1331. Nakamura, M., McCarley, R.W., Kubicki, M., Dickey, C.C., Niznikiewicz, M.A., Voglmaier, M.M., Seidman, L.J., Maier, S.E., Westin, C.F., Kikinis, R., Shenton, M.E., 2005. Frontotemporal disconnectivity in schizotypal personality disorder: a diffusion tensor imaging study. Biol. Psychiatry 58, 468–478.
237
Ozgen, H., Schrimpf, W., Hendrix, J., de Jonge, J.C., Lamb, D.C., Hoekstra, D., Kahya, N., Baron, W., 2014. The lateral membrane organization and dynamics of myelin proteins PLP and MBP are dictated by distinct galactolipids and the extracellular matrix. PLoS One 9, e101834. Radhu, N., Garcia Dominguez, L., Farzan, F., Richter, M.A., Semeralul, M.O., Chen, R., Fitzgerald, P.B., Daskalakis, Z.J., 2015. Evidence for inhibitory deficits in the prefrontal cortex in schizophrenia. Brain 138, 483–497. Raum, H., Dietsche, B., Nagels, A., Witt, S.H., Rietschel, M., Kircher, T., Krug, A., 2015. A genome-wide supported psychiatric risk variant in NCAN influences brain function and cognitive performance in healthy subjects. Hum. Brain Mapp. 36, 378–390. Schultz, C.C., Mühleisen, T.W., Nenadic, I., Koch, K., Wagner, G., Schachtzabel, C., Siedek, F., Nöthen, M.M., Rietschel, M., Deufel, T., Kiehntopf, M., Cichon, S., Reichenbach, J.R., Sauer, H., Schlösser, R.G., 2014. Common variation in NCAN, a risk factor for bipolar disorder and schizophrenia, influences local cortical folding in schizophrenia. Psychol. Med. 44, 811–820. Uranova, N.A., Vikhreva, O.V., Rachmanova, V.I., Orlovskaya, D.D., 2011. Ultrastructural alterations of myelinated fibers and oligodendrocytes in the prefrontal cortex in schizophrenia: a postmortem morphometric study. Schizophr. Res. Treat. 2011, 325789. Wood, P.L., 2014. Accumulation of N-acylphosphatidylserines and N-acylserines in the frontal cortex in schizophrenia. Neurotransmitter 1, e263. Wood, P.L., Shirley, N.R., 2013. Lipidomics analysis of postmortem interval: preliminary evaluation of human skeletal muscle. Metabolomics 3, 3. Wood, P.L., Filiou, M.D., Otte, D.M., Zimmer, A., Turck, C.W., 2014a. Lipidomics reveals dysfunctional glycosynapses in schizophrenia and the G72/G30 transgenic mouse. Schizophr. Res. 159, 365–369. Wood, P.L., Phillipps, A., Woltjer, R.L., Kaye, J.A., Quinn, J.F., 2014b. Increased lysophosphatidylethanolamine and diacylglycerol levels in Alzheimer's disease plasma. JSM Alzheimer's Disease and Related Dementia 1, 1001. Wood, P.L., Unfried, G., Whitehead, W., Phillipps, A., Wood, J.A., 2015. Dysfunctional plasmalogen dynamics in the plasma and platelets of patients with schizophrenia. Schizophr. Res. 161, 506–510. Yamamoto, K., Miyazaki, K., Higashi, S., 2014. Pericellular proteolysis by matrix metalloproteinase-7 is differentially modulated by cholesterol sulfate, sulfatide, and cardiolipin. FEBS J. 281, 3346–3356.