A starring role for microglia in brain sex differences

Neuroscientist

Volumn 21, Issue 3, 2015, Pages 306-321

  Lenz, Kathryn M ^a   McCarthy, Margaret M ^b  

^a OHIO STATE UNIVERSITY   (United States)

^b UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

Author keywords

cytokine; development; hormone; immune; inflammation; microglia; sex; sex differences

Indexed keywords

AMPA RECEPTOR; CASPASE 3; CD11B ANTIGEN; CYCLIC AMP; CYCLIC AMP DEPENDENT PROTEIN KINASE; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; CYTOKINE; ESTRADIOL; ESTROGEN; ESTROGEN RECEPTOR ALPHA; GAMMA INTERFERON; GROWTH FACTOR; INTEGRIN; KILLER CELL ACTIVATING RECEPTOR ASSOCIATED PROTEIN; MACROPHAGE INFLAMMATORY PROTEIN 1BETA; MACROPHAGE INFLAMMATORY PROTEIN 3ALPHA; MICRORNA; PHOSPHATIDYLSERINE; PROSTAGLANDIN; PROSTAGLANDIN E2; SEROTONIN TRANSPORTER; STEROID; TESTIS DETERMINING FACTOR; TESTOSTERONE; TRANSFORMING GROWTH FACTOR BETA;

AGGRESSION; AMYGDALOID NUCLEUS; ANDROGEN SYNTHESIS; ANTIINFLAMMATORY ACTIVITY; ANXIETY DISORDER; APOPTOSIS; ASPERGER SYNDROME; ATTENTION DEFICIT DISORDER; AUTISM; AUTOIMMUNE DISEASE; BACTERIAL INFECTION; BIPOLAR DISORDER; BRAIN; BRAIN DEVELOPMENT; BRAIN REGION; CELL PROLIFERATION; CELL SURVIVAL; CEREBRAL PALSY; CEREBROVASCULAR ACCIDENT; CHRONIC INFLAMMATION; COGNITION; DENDRITIC SPINE; DEVELOPMENTAL DISORDER; DISEASE PREDISPOSITION; DYSLEXIA; EMBRYO DEVELOPMENT; ENVIRONMENTAL FACTOR; FEMALE; FEMININITY; GENE EXPRESSION REGULATION; GENOTYPE ENVIRONMENT INTERACTION; GILLES DE LA TOURETTE SYNDROME; GONAD DEVELOPMENT; HEMATOPOIESIS; HIPPOCAMPUS; HORMONE ACTION; HUMAN; INCIDENCE; INNATE IMMUNITY; INTERPERSONAL COMMUNICATION; LEARNING DISORDER; LONG TERM DEPRESSION; LONG TERM POTENTIATION; MAJOR DEPRESSION; MALE; MASCULINITY; MAST CELL; MEDIATOR RELEASE; MENOPAUSE; MICROGLIA; MOOD DISORDER; MYELOID PROGENITOR CELL; NERVE CELL PLASTICITY; NERVE DEGENERATION; NERVOUS SYSTEM DEVELOPMENT; NERVOUS SYSTEM INFLAMMATION; NEUROIMMUNOLOGY; NEUROLOGIC DISEASE; NEUROTRANSMISSION; NONHUMAN; PERINATAL PERIOD; PHAGOCYTOSIS; POSTTRAUMATIC STRESS DISORDER; PREOPTIC AREA; PRIORITY JOURNAL; REVIEW; SCHIZOPHRENIA; SEX DETERMINATION; SEX DIFFERENCE; SEX DIFFERENTIATION; SEXUAL BEHAVIOR; SOCIAL BEHAVIOR; SPINAL CORD INJURY; SUBVENTRICULAR ZONE; SYNAPTIC TRANSMISSION; SYNAPTOGENESIS; TESTIS DEVELOPMENT; TRAUMATIC BRAIN INJURY; X CHROMOSOME; X CHROMOSOME INACTIVATION; Y CHROMOSOME; YOLK SAC; ANIMAL; CELL DEATH; GROWTH, DEVELOPMENT AND AGING; IMMUNOLOGY; PHYSIOLOGY; SEXUAL DEVELOPMENT;

ANIMALS; BRAIN; CELL DEATH; FEMALE; HUMANS; MALE; MICROGLIA; NEURONAL PLASTICITY; SEX CHARACTERISTICS; SEX DIFFERENTIATION; SEXUAL BEHAVIOR;

EID: 84930342622     PISSN: 10738584     EISSN: 10894098     Source Type: Journal    
DOI: 10.1177/1073858414536468     Document Type: Review

References (142)

1. Aguzzi A, Barres BA, Bennett ML. Microglia: scapegoat, saboteur, or something else?. Science. 2013 ; 339: 156-61
2. Ahokas A, Kaukoranta J, Wahlbeck K, Aito M. Estrogen deficiency in severe postpartum depression: successful treatment with sublingual physiologic 17β-estradiol: a preliminary study. J Clin Psychiatry. 2001 ; 62: 332-6
3. Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci. 2007 ; 10: 1538-43
4. Alliot F, Godin I, Pessac B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res. 1999 ; 117: 145-52
5. Amateau SK, McCarthy MM. A novel mechanism of dendritic spine plasticity involving estradiol induction of prostaglandin-E2. J Neurosci. 2002a ; 22: 8586-96
6. Amateau SK, McCarthy MM. Sexual differentiation of astrocyte morphology in the developing rat preoptic area. J Neuroendocrinol. 2002b ; 14: 904-10
7. Amateau SK, McCarthy MM. Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior. Nat Neurosci. 2004 ; 7: 643-50
8. Angst J, Gamma A, Gastpar M, Lépine J-P, Mendlewicz J, Tylee A. Gender differences in depression. Epidemiological findings from the European DEPRES I and II studies. Eur Arch Psychiatry Clin Neurosci. 2002 ; 252: 201-9
9. Arnold AP, Chen X. What does the "four core genotypes" mouse model tell us about sex differences in the brain and other tissues?. Front Neuroendocrinol. 2009 ; 30: 1-9
10. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011 ; 25: 40-5
11. Atladóttir HO, Thorsen P, Schendel DE, Østergaard L, Lemcke S, Parner ET. Association of hospitalization for infection in childhood with diagnosis of autism spectrum disorders: a Danish cohort study. Arch Pediatr Adolesc Med. 2010 ; 164: 470-7
12. Baganz NL, Blakely RD. A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem Neurosci. 2013 ; 4: 48-63
13. Baron-Cohen S. The extreme male brain theory of autism. Trends Cogn Sci. 2002 ; 6: 248-254
14. Baron-Cohen S, Scott FJ, Allison C, Williams J, Bolton P, Matthews FE. Prevalence of autism-spectrum conditions: UK school-based population study. Br J Psychiatry. 2009 ; 194: 500-9
15. Barron KD. The microglial cell. A historical review. J Neurol Sci. 1995 ; 134: 57-68
16. Bialas AR, Stevens B. TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci. 2013 ; 16: 1773-82
17. Bilousova TV, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet. 2009 ; 46: 94-102
18. Borrell J, Vela JM, Arévalo-Martin A, Molina-Holgado E, Guaza C. Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia. Neuropsychopharmacology. 2002 ; 26: 204-15
19. Breslau N, Davis GC, Andreski P, Peterson EL, Schultz LR. Sex differences in posttraumatic stress disorder. Arch Gen Psychiatry. 1997 ; 54: 1044-8
20. Brown CM, Mulcahey TA, Filipek NC, Wise PM. Production of proinflammatory cytokines and chemokines during neuroinflammation: novel roles for estrogen receptors alpha and beta. Endocrinology. 2010 ; 151: 4916-25
21. Capuron L, Ravaud A. Prediction of the depressive effects of interferon α therapy by the patient's initial affective state. N Engl J Med. 1999 1370 ; 340 :
22. Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005 ; 434: 400-4
23. Collaer ML, Hines M. Human behavioral sex differences: a role for gonadal hormones during early development?. Psychol Bull. 1995 ; 118: 55-107
24. Costello DA, Lyons A, Denieffe S, Browne TC, Cox FF, Lynch MA. Long term potentiation is impaired in membrane glycoprotein CD200-deficient mice: a role for Toll-like receptor activation. J Biol Chem. 2011 ; 286: 34722-32
25. Crain JM, Nikodemova M, Watters JJ. Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice. J Neurosci Res. 2013 ; 91: 1143-51
26. Cunningham CL, Martínez-Cerdeño V, Noctor SC. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci. 2013 ; 33: 4216-33
27. Czlonkowska A, Ciesielska A, Gromadzka G. Gender differences in neurological disease. Endocrine. 2006 ; 29: 243-56
28. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008 ; 9: 46-56
29. Du S, Itoh N, Askarinam S, Hill H, Arnold AP, Voskuhl RR. XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2014 ; 111: 2806-11
30. Dunn AJ, Swiergiel AH, de Beaurepaire R. Cytokines as mediators of depression: what can we learn from animal studies?. Neurosci Biobehav Rev. 2005 ; 29: 891-909
31. Ehninger D, Kempermann G. Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex. Cereb Cortex. 2003 ; 13: 845-51
32. Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry. 2010 ; 68: 748-54
33. Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol. 2008 ; 8: 737-44
34. Fombonne E. Epidemiological trends in rates of autism. Mol Psychiatry. 2002 ; 7: S4-6
35. Forest MG, Cathiard AM, Bertrand JA. Evidence of testicular activity in early infancy. J Clin Endocrinol Metab. 1973 ; 37: 148-51
36. Forrest CM, Khalil OS, Pisar M, Smith RA, Darlington LG, Stone TW. Prenatal activation of Toll-like receptors-3 by administration of the viral mimetic poly(I:C) changes synaptic proteins, N-methyl-D-aspartate receptors and neurogenesis markers in offspring. Mol Brain. 2012 ; 5: 22
37. Freeman E, Sammel M, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry. 2006 ; 63: 375-82
38. Garzon R, Calin GA, Croce CM. MicroRNAs in cancer. Annu Rev Med. 2009 ; 60: 167-79
39. Gatewood JD, Wills A, Shetty S, Xu J, Arnold AP, Burgoyne PS. Sex chromosome complement and gonadal sex influence aggressive and parental behaviors in mice. J Neurosci. 2006 ; 26: 2335-42
40. Geier D, Kern J, King P, Sykes LK, Geier MR. An evaluation of the role and treatment of elevated male hormones in autism spectrum disorders. Acta Neurobio Exp (Wars). 2012 ; 72: 1-17
41. Gendrel D, Chaussain JL, Roger M, Job JC. Simultaneous postnatal rise of plasma LH and testosterone in male infants. J Pediatr. 1980 ; 97: 600-2
42. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010 ; 330: 841-5
43. Goodfellow PN, Lovell-Badge R. SRY and sex determination in mammals. Annu Rev Genet. 1993 ; 27: 71-92
44. Gorski RA, Harlan RE, Jacobson CD, Shryne JE, Southam AM. Evidence for the existence of a sexually dimorphic nucleus in the preoptic area of the rat. J Comp Neurol. 1980 ; 193: 529-39
45. Gregory CD, Pound JD. Cell death in the neighbourhood: direct microenvironmental effects of apoptosis in normal and neoplastic tissues. J Pathol. 2011 ; 223: 177-94
46. Hanisch U-K, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007 ; 10: 1387-94
47. Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation. 2008 ; 5: 15
48. Hickey WF, Vass K, Lassmann H. Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. J Neuropathol Exp Neurol. 1992 ; 51: 246-56
49. Honda S, Harada N, Ito S, Takagi Y, Maeda S. Disruption of sexual behavior in male aromatase-deficient mice lacking exons 1 and 2 of the cyp19 gene. Biochem Biophys Res Commun. 1998 ; 252: 445-9
50. Huo L, Straub RE, Roca C, Schmidt PJ, Shi K, Vakkalanka R. Risk for premenstrual dysphoric disorder is associated with genetic variation in ESR1, the estrogen receptor alpha gene. Biol Psychiatry. 2007 ; 62: 925-33
51. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997 ; 84: 223-43
52. Jacquemont S, Coe BP, Hersch M, Duyzend MH, Krumm N, Bergmann S. A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders. Am J Hum Genet. 2014 ; 94: 415-25
53. Järlestedt K, Naylor AS, Dean J, Hagberg H, Mallard C. Decreased survival of newborn neurons in the dorsal hippocampus after neonatal LPS exposure in mice. Neuroscience. 2013 ; 253: 21-8
54. Khalil M, Ronda J, Weintraub M, Jain K, Silver R, Silverman A-J. Brain mast cell relationship to neurovasculature during development. Brain Res. 2007 ; 1171: 18-29
55. Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci. 2009 ; 29: 13435-44
56. Kirsten TB, Taricano M, Flório JC, Palermo-Neto J, Bernardi MM. Prenatal lipopolysaccharide reduces motor activity after an immune challenge in adult male offspring. Behav Brain Res. 2010 ; 211: 77-82
57. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996 ; 19: 312-8
58. Kudwa AE, Bodo C, Gustafsson J-A, Rissman EF. A previously uncharacterized role for estrogen receptor beta: defeminization of male brain and behavior. Proc Natl Acad Sci U S A. 2005 ; 102: 4608-12
59. Lambracht-Hall M, Dimitriadou V, Theoharides TC. Migration of mast cells in the developing rat brain. Brain Res Dev Brain Res. 1990 ; 56: 151-9
60. Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990 ; 39: 151-70
61. Lenz KM, Nugent BM, Haliyur R, McCarthy MM. Microglia are essential to masculinization of brain and behavior. J Neurosci. 2013 ; 33: 2761-72
62. Lenz KM, Nugent BM, McCarthy MM. Sexual differentiation of the rodent brain: dogma and beyond. Front Neurosci. 2012 ; 6: 26
63. Lenz KM, Wright CL, Martin RC, McCarthy MM. Prostaglandin E2 regulates AMPA receptor phosphorylation and promotes membrane insertion in preoptic area neurons and glia during sexual differentiation. PLoS One. 2011 ; 6: e18500
64. Lenzlinger PM, Hans VH, Jöller-Jemelka HI, Trentz O, Morganti-Kossmann MC, Kossmann T. Markers for cell-mediated immune response are elevated in cerebrospinal fluid and serum after severe traumatic brain injury in humans. J Neurotrauma. 2001 ; 18: 479-89
65. Li Q, Cheung C, Wei R, Hui ES, Feldon J, Meyer U. Prenatal immune challenge is an environmental risk factor for brain and behavior change relevant to schizophrenia: evidence from MRI in a mouse model. PLoS One. 2009 ; 4: e6354
66. Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li X-M. Elevated immune response in the brain of autistic patients. J Neuroimmunol. 2009 ; 207: 111-6
67. Libert C, Dejager L, Pinheiro I. The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol. 2010 ; 10: 594-604
68. Lieblein-Boff JC, McKim DB, Shea DT, Wei P, Deng Z, Sawicki C. Neonatal E. coli infection causes neuro-behavioral deficits associated with hypomyelination and neuronal sequestration of iron. J Neurosci. 2013 ; 33: 16334-45
69. Lin A, Kenis G, Bignotti S, Tura GJ, De Jong R, Bosmans E. The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr Res. 1998 ; 32: 9-15
70. Lin Y-L, Lin S-Y, Wang S. Prenatal lipopolysaccharide exposure increases anxiety-like behaviors and enhances stress-induced corticosterone responses in adult rats. Brain Behav Immun. 2012 ; 26: 459-68
71. Loram LC, Sholar PW, Taylor FR, Wiesler JL, Babb JA, Strand KA. Sex and estradiol influence glial pro-inflammatory responses to lipopolysaccharide in rats. Psychoneuroendocrinology. 2012 ; 37: 1688-99
72. Makino M, Kitano Y, Komiyama C, Hirohashi M, Kohno M, Moriyama M. Human interferon-α induces immobility in the mouse forced swimming test: involvement of the opioid system. Brain Res. 2000 ; 852: 482-4
73. Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun. 2012 ; 26: 607-16
74. Marín-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M. Microglia promote the death of developing Purkinje cells. Neuron. 2004 ; 41: 535-47
75. McCarthy MM. Estradiol and the developing brain. Physiol Rev. 2008 ; 88: 91-124
76. Meyer U, Feldon J. Neural basis of psychosis-related behaviour in the infection model of schizophrenia. Behav Brain Res. 2009 ; 204: 322-34
77. Meyer U, Nyffeler M, Schwendener S, Knuesel I, Yee BK, Feldon J. Relative prenatal and postnatal maternal contributions to schizophrenia-related neurochemical dysfunction after in utero immune challenge. Neuropsychopharmacology. 2008 ; 33: 441-56
78. Molloy C a, Morrow AL, Meinzen-Derr J, Schleifer K, Dienger K, Manning-Courtney P. Elevated cytokine levels in children with autism spectrum disorder. J Neuroimmunol. 2006 ; 172: 198-205
79. Müller N, Schwarz MJ. COX-2 inhibition in schizophrenia and major depression. Curr Pharm Des. 2008 ; 14: 1452-65
80. Nakanishi M, Niidome T, Matsuda S, Akaike A, Kihara T, Sugimoto H. Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells. Eur J Neurosci. 2007 ; 25: 649-58
81. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005 ; 308: 1314-8
82. Nimmervoll B, White R, Yang J-W, An S, Henn C, Sun J-J. LPS-induced microglial secretion of TNFα increases activity-dependent neuronal apoptosis in the neonatal cerebral cortex. Cereb Cortex. 2013 ; 23: 1742-55
83. Nolen-Hoeksema S. Sex differences in unipolar depression: evidence and theory. Psychol Bull. 1987 ; 101: 259-82
84. O'Brien SM, Scott LV, Dinan TG. Cytokines: abnormalities in major depression and implications for pharmacological treatment. Hum Psychopharmacol. 2004 ; 19: 397-403
85. Ogawa S, Chester AE, Hewitt SC, Walker VR, Gustafsson JA, Smithies O. Abolition of male sexual behaviors in mice lacking estrogen receptors α and β (αβERKO). Proc Natl Acad Sci U S A. 2000 ; 97: 14737-41
86. Olah M, Ping G, De Haas AH, Brouwer N, Meerlo P, Van Der Zee EA. Enhanced hippocampal neurogenesis in the absence of microglia T cell interaction and microglia activation in the murine running wheel model. Glia. 2009 ; 57: 1046-61
87. Paolicelli R, Bolasco G, Pagani F, Maggi L. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011 ; 333: 1456-8
88. Parboosing R, Bao Y, Shen L, Schaefer CA, Brown AS. Gestational influenza and bipolar disorder in adult offspring. JAMA Psychiatry. 2013 ; 70: 677-85
89. Patterson PH. Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res. 2009 ; 204: 313-21
90. Pinheiro I, Dejager L, Libert C. X-chromosome-located microRNAs in immunity: might they explain male/female differences? The X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females. Bioessays. 2011 ; 33: 791-802
91. Quinn JJ, Hitchcott PK, Umeda EA, Arnold AP, Taylor JR. Sex chromosome complement regulates habit formation. Nat Neurosci. 2007 ; 10: 1398-400
92. Radewicz K, Garey LJ, Gentleman SM, Reynolds R. Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. J Neuropathol Exp Neurol. 2000 ; 59: 137-50
93. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006 ; 27: 24-31
94. Ravichandran KS. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity. 2011 ; 35: 445-55
95. Reyes FI, Winter JSD, Faiman C. Studies on human sexual development. I. Fetal gonadal and adrenal sex steroids. J Clin Endocrinol Metab. 1973 ; 37: 74-8
96. Robinson EB, Lichtenstein P, Anckarsäter H, Happé F, Ronald A. Examining and interpreting the female protective effect against autistic behavior. Proc Natl Acad Sci U S A. 2013 ; 110: 5258-62
97. Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA. CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci. 2011 ; 31: 16241-50
98. Romero E, Guaza C, Castellano B, Borrell J. Ontogeny of sensorimotor gating and immune impairment induced by prenatal immune challenge in rats: implications for the etiopathology of schizophrenia. Mol Psychiatry. 2010 ; 15: 372-83
99. Rousset CI, Chalon S, Cantagrel S, Bodard S, Andres C, Gressens P. Maternal exposure to LPS induces hypomyelination in the internal capsule and programmed cell death in the deep gray matter in newborn rats. Pediatr Res. 2006 ; 59: 428-33
100. Saetre P, Emilsson L, Axelsson E, Kreuger J, Lindholm E, Jazin E. Inflammation-related genes up-regulated in schizophrenia brains. BMC Psychiatry. 2007 ; 7: 46
101. Saijo K, Collier JG, Li AC, Katzenellenbogen JA, Glass CK. An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation. Cell. 2011 ; 145: 584-95
102. Saxena V, Ramdas S, Ochoa CR, Wallace D, Bhide P, Kohane I. Structural, genetic, and functional signatures of disordered neuro-immunological development in autism spectrum disorder. PLoS One. 2012 ; 7: e48835
103. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012 ; 74: 691-705
104. Schmidt HD, Shelton RC, Duman RS. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology. 2011 ; 36: 2375-94
105. Schwarz E, Guest PC, Rahmoune H, Wang L, Levin Y, Ingudomnukul E. Sex-specific serum biomarker patterns in adults with Asperger's syndrome. Mol Psychiatry. 2011 ; 16: 1213-20
106. Schwarz JM, Sholar PW, Bilbo SD. Sex differences in microglial colonization of the developing rat brain. J Neurochem. 2012 ; 120: 948-63
107. Selmi C. The X in sex: how autoimmune diseases revolve around sex chromosomes. Best Pract Res Clin Rheumatol. 2008 ; 22: 913-22
108. Shigemoto-Mogami Y, Hoshikawa K, Goldman JE, Sekino Y, Sato K. Microglia enhance neurogenesis and oligodendrogenesis in the early postnatal subventricular zone. J Neurosci. 2014 ; 34: 2231-43
109. Sicotte NL, Liva SM, Klutch R, Pfeiffer P, Bouvier S, Odesa S. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol. 2002 ; 52: 421-8
110. Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 2010 ; 7: 483-95
111. Silver R, Curley JP. Mast cells on the mind: new insights and opportunities. Trends Neurosci. 2013 ; 36: 513-21
112. Silverman AJ, Millar RP, King JA, Zhuang X, Silver R. Mast cells with gonadotropin-releasing hormone-like immunoreactivity in the brain of doves. Proc Natl Acad Sci U S A. 1994 ; 91: 3695-9
113. Silverman AJ, Sutherland AK, Wilhelm M, Silver R. Mast cells migrate from blood to brain. J Neurosci. 2000 ; 20: 401-8
114. Soldan SS, Alvarez Retuerto AI, Sicotte NL, Voskuhl RR. Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol. 2003 ; 171: 6267-74
115. Spolarics Z. The X-files of inflammation: cellular mosaicism of X-linked polymorphic genes and the female advantage in the host response to injury and infection. Shock. 2007 ; 27: 597-604
116. Steiner J, Mawrin C, Ziegeler A, Bielau H, Ullrich O, Bernstein H-G. Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired cerebral lateralization. Acta Neuropathol. 2006 ; 112: 305-16
117. Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein H-G, Sarnyai Z. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission?. J Neuroinflammation. 2011 ; 8: 94
118. Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry. 2013 ; 70: 49-58
119. Takao K, Kobayashi K, Hagihara H, Ohira K, Shoji H, Hattori S. Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia. Neuropsychopharmacology. 2013 ; 38: 1409-25
120. Taylor P V, Veenema AH, Paul MJ, Bredewold R, Isaacs S, de Vries GJ. Sexually dimorphic effects of a prenatal immune challenge on social play and vasopressin expression in juvenile rats. Biol Sex Differ. 2012 ; 3: 15
121. Tetreault NA, Hakeem AY, Jiang S, Williams BA, Allman E, Wold BJ. Microglia in the cerebral cortex in autism. J Autism Dev Disord. 2012 ; 42: 2569-84
122. Tonelli LH, Holmes A, Postolache TT. Intranasal immune challenge induces sex-dependent depressive-like behavior and cytokine expression in the brain. Neuropsychopharmacology. 2008 ; 33: 1038-48
123. Tremblay M, Lowery R, Majewska A. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 2010 ; 8: e1000527
124. van de Beek C, Thijssen JHH, Cohen-Kettenis PT, van Goozen SHM, Buitelaar JK. Relationships between sex hormones assessed in amniotic fluid, and maternal and umbilical cord serum: what is the best source of information to investigate the effects of fetal hormonal exposure?. Horm Behav. 2004 ; 46: 663-9
125. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 ; 57: 67-81
126. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011 ; 474: 380-4
127. Vukovic J, Colditz MJ, Blackmore DG, Ruitenberg MJ, Bartlett PF. Microglia modulate hippocampal neural precursor activity in response to exercise and aging. J Neurosci. 2012 ; 32: 6435-43
128. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci. 2009 ; 29: 3974-80
129. Wakselman S, Béchade C, Roumier A, Bernard D, Triller A, Bessis A. Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. J Neurosci. 2008 ; 28: 8138-43
130. Walker LG, Walker MB, Heys SD, Lolley J, Wesnes K, Eremin O. The psychological and psychiatric effects of rIL-2 therapy: a controlled clinical trial. Psychooncology. 1997 ; 6: 290-301
131. Walton N, Sutter B, Laywell E, Levkoff LH, Kearns SM, Marshall GP. Microglia instruct subventricular zone neurogenesis. Glia. 2006 ; 54: 815-25
132. Werling DM, Geschwind DH. Sex differences in autism spectrum disorders. Curr Opin Neurol. 2013 ; 26: 146-53
133. Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001 ; 2: 777-80
134. Wohleb ES, McKim DB, Shea DT, Powell ND, Tarr AJ, Sheridan JF. Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain. Biol Psychiatry Epub Dec 11. 2013 ;:
135. Wright CL, Burks SR, McCarthy MM. Identification of prostaglandin E2 receptors mediating perinatal masculinization of adult sex behavior and neuroanatomical correlates. Dev Neurobiol. 2008 ; 68: 1406-19
136. Wright CL, McCarthy MM. Prostaglandin E2-induced masculinization of brain and behavior requires protein kinase A, AMPA/kainate, and metabotropic glutamate receptor signaling. J Neurosci. 2009 ; 29: 13274-82
137. Wu H, Luo J, Yu H, Rattner A, Mo A, Wang Y. Cellular resolution maps of X chromosome inactivation: implications for neural development, function, and disease. Neuron. 2014 ; 81: 103-19
138. Wu T-H, Lin C-H. IL-6 mediated alterations on immobile behavior of rats in the forced swim test via ERK1/2 activation in specific brain regions. Behav Brain Res. 2008 ; 193: 183-91
139. Xue J, Schmidt S V, Sander J, Draffehn A, Krebs W, Quester I. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014 ; 40: 274-88
140. Zechner U, Wilda M, Kehrer-Sawatzki H, Vogel W, Fundele R, Hameister H. A high density of X-linked genes for general cognitive ability: a run-away process shaping human evolution?. Trends Genet. 2001 ; 17: 697-701
141. Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci. 2014 ; 17: 400-6
142. Zhong Y, Zhou L-J, Ren W-J, Xin W-J, Li Y-Y, Zhang T. The direction of synaptic plasticity mediated by C-fibers in spinal dorsal horn is decided by Src-family kinases in microglia: the role of tumor necrosis factor-α. Brain Behav Immun. 2010 ; 24: 874-80