Protein Expression in the Nucleus Accumbens of Rats Exposed to Developmental Vitamin D Deficiency

Introduction Developmental vitamin D (DVD) deficiency is a candidate risk factor for schizophrenia. Animal models have confirmed that DVD deficiency is associated with a range of altered genomic, proteomic, structural and behavioural outcomes in the rat. Because the nucleus accumbens has been implicated in neuropsychiatric disorders, in the current study we examined protein expression in this region in adult rats exposed to DVD deficiency Methods Female Sprague Dawley rats were maintained on a vitamin D deficient diet for 6 weeks, mated and allowed to give birth, after which a diet containing vitamin D was reintroduced. Male adult offspring (n = 8) were compared to control male (n = 8). 2-D gel electrophoresis-based proteomics and mass spectroscopy were used to investigate differential protein expression. Results There were 35 spots, mapped to 33 unique proteins, which were significantly different between the two groups. Of these, 22 were down-regulated and 13 up-regulated. The fold changes were uniformly small, with the largest FC being −1.67. Within the significantly different spots, three calcium binding proteins (calbindin1, calbindin2 and hippocalcin) were altered. Other proteins associated with DVD deficiency related to mitochondrial function, and the dynamin-like proteins. Conclusions Developmental vitamin D deficiency was associated with subtle changes in protein expression in the nucleus accumbens. Disruptions in pathways related to calcium-binding proteins and mitochondrial function may underlie some of the behavioural features associated with animal models of developmental vitamin D deficiency

[1]  A. Parent,et al.  Chemical anatomy of the human ventral striatum and adjacent basal forebrain structures , 2003, The Journal of comparative neurology.

[2]  D. Eyles,et al.  Vitamin D deficiency during various stages of pregnancy in the rat; its impact on development and behaviour in adult offspring , 2007, Psychoneuroendocrinology.

[3]  A. Goldberg,et al.  Pathway for Degradation of Peptides Generated by Proteasomes , 2004, Journal of Biological Chemistry.

[4]  H. Raventós,et al.  Malic enzyme 2 and susceptibility to psychosis and mania , 2007, Psychiatry Research.

[5]  P. Goldman-Rakic,et al.  Internalization of D2 dopamine receptors is clathrin‐dependent and select to dendro–axonic appositions in primate prefrontal cortex , 2006, The European journal of neuroscience.

[6]  S. Saha,et al.  The incidence and prevalence of schizophrenia varies with latitude , 2006, Acta psychiatrica Scandinavica.

[7]  J. Pierri,et al.  Gene Expression Profiling Reveals Alterations of Specific Metabolic Pathways in Schizophrenia , 2002, The Journal of Neuroscience.

[8]  M. M. Bradford A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[9]  B. Ames,et al.  Is there convincing biological or behavioral evidence linking vitamin D deficiency to brain dysfunction? , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  A. Mackay-Sim,et al.  Maternal vitamin D depletion alters neurogenesis in the developing rat brain , 2007, International Journal of Developmental Neuroscience.

[11]  C. Harper,et al.  Differential protein expression in the prefrontal white matter of human alcoholics: a proteomics study , 2006, Molecular Psychiatry.

[12]  Kyla Pennington,et al.  Proteomic analysis of the anterior cingulate cortex in the major psychiatric disorders: Evidence for disease‐associated changes , 2006, Proteomics.

[13]  K. Cunningham,et al.  Estrogen regulation of gene expression in the brain: a possible mechanism altering the response to psychostimulants in female rats. , 2002, Brain research. Molecular brain research.

[14]  A. Mackay-Sim,et al.  Developmental Vitamin D3 deficiency alters the adult rat brain , 2005, Brain Research Bulletin.

[15]  L. Juliano,et al.  Calcium modulates endopeptidase 24.15 (EC 3.4.24.15) membrane association, secondary structure and substrate specificity , 2005, The FEBS journal.

[16]  Svetlana V. Kyosseva,et al.  Differential expression of mitogen-activated protein kinases and immediate early genes fos and jun in thalamus in schizophrenia , 2004, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[17]  Marquis P Vawter,et al.  Microarray screening of lymphocyte gene expression differences in a multiplex schizophrenia pedigree , 2004, Schizophrenia Research.

[18]  Michael X. Cohen,et al.  Deep Brain Stimulation to Reward Circuitry Alleviates Anhedonia in Refractory Major Depression , 2008, Neuropsychopharmacology.

[19]  G. Reynolds,et al.  Neuronal calcium-binding proteins and schizophrenia , 2002, Schizophrenia Research.

[20]  M. Escamilla Variation in the malic enzyme 2 gene: implications for the pharmacogenomics of psychotic disorders. , 2007, Pharmacogenomics.

[21]  A. Young,et al.  The interpretation of the measurement of nucleus accumbens dopamine by in vivo dialysis: the kick, the craving or the cognition? , 2003, Neuroscience & Biobehavioral Reviews.

[22]  C. Nemeroff,et al.  Neurotensin: Role in psychiatric and neurological diseases , 2006, Peptides.

[23]  L. Scorrano Multiple functions of mitochondria-shaping proteins. , 2007, Novartis Foundation symposium.

[24]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[25]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[26]  P. Račay,et al.  Deficiency in parvalbumin, but not in calbindin D-28k upregulates mitochondrial volume and decreases smooth endoplasmic reticulum surface selectively in a peripheral, subplasmalemmal region in the soma of Purkinje cells , 2006, Neuroscience.

[27]  S. Kapur,et al.  Half a century of antipsychotics and still a central role for dopamine D2 receptors , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[28]  Daniel R. Weinberger,et al.  Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia , 2004, Neurochemical Research.

[29]  A. Mackay-Sim,et al.  Vitamin d3 and brain development , 2003, Neuroscience.

[30]  M. Holick,et al.  Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. , 1988, The Journal of clinical endocrinology and metabolism.

[31]  Y. Liu,et al.  New insights into the function and regulation of vitamin D target proteins , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[32]  D. Eyles,et al.  Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats , 2005, Behavioural Brain Research.

[33]  L. Lagnado,et al.  Endocytosis at the synaptic terminal , 2003, The Journal of physiology.

[34]  D. Eyles,et al.  Developmental Vitamin D Deficiency Alters MK 801-Induced Hyperlocomotion in the Adult Rat: An Animal Model of Schizophrenia , 2006, Biological Psychiatry.

[35]  Ann E. Kelley,et al.  The structural basis for mapping behavior onto the ventral striatum and its subdivisions , 2008, Brain Structure and Function.

[36]  D. Senitz,et al.  Increased volume of the nucleus accumbens in schizophrenia , 2001, Journal of Neural Transmission.

[37]  A. Mackay-Sim,et al.  Transient prenatal Vitamin D deficiency is associated with hyperlocomotion in adult rats , 2004, Behavioural Brain Research.

[38]  A. Grace,et al.  Regulation of firing of dopaminergic neurons and control of goal-directed behaviors , 2007, Trends in Neurosciences.

[39]  R. L. Moss,et al.  Modulation of mesolimbic dopaminergic activity over the rat estrous cycle , 1997, Neuroscience Letters.

[40]  T. Hashimoto,et al.  Deciphering the disease process of schizophrenia: the contribution of cortical GABA neurons. , 2007, International review of neurobiology.

[41]  P. Joyce,et al.  Psychotic disorders. , 2020, The New Zealand medical journal.

[42]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[43]  E. Torrey,et al.  Season of birth effect and latitude: A systematic review and meta-analysis of Northern hemisphere schizophrenia studies , 2000, Schizophrenia Research.

[44]  K. Fuxe,et al.  Mesolimbic dopamine and cortico-accumbens glutamate afferents as major targets for the regulation of the ventral striato-pallidal GABA pathways by neurotensin peptides , 2007, Brain Research Reviews.

[45]  A. Nairn,et al.  Recent advances in neuroproteomics. , 2007, Current opinion in molecular therapeutics.

[46]  J. Mcgrath Hypothesis: Is low prenatal vitamin D a risk-modifying factor for schizophrenia? , 1999, Schizophrenia Research.

[47]  D. Eyles,et al.  Maternal vitamin D3 deprivation and the regulation of apoptosis and cell cycle during rat brain development. , 2004, Brain research. Developmental brain research.

[48]  A. Mackay-Sim,et al.  Developmental vitamin D deficiency alters the expression of genes encoding mitochondrial, cytoskeletal and synaptic proteins in the adult rat brain , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[49]  A. Mackay-Sim,et al.  Developmental vitamin D deficiency alters brain protein expression in the adult rat: Implications for neuropsychiatric disorders , 2007, Proteomics.

[50]  E. Torrey,et al.  A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia. , 2003, Schizophrenia bulletin.