found in individuals with schizophrenia. As a consequence,
synaptic transmission and plasticity are affected in young
adulthood, when refinement of synaptic connections requires
higher activity potentially leading to a loss of synaptic plasticity
(Fatemi and Folsom, 2009).
These findings portray an intricate process by which foetal
inflammation perturbs neuronal patterning and cortical
development contributing to cognitive and/or psychotic
manifestations later in adulthood. Such a process acts upon
a number of different pathways, a number of which then have
additional roles in mediating some of the experience-
dependent plasticity in the adult brain. Based on these results,
we surmise that the formation of neuronal networks in
offspring from LPS-injected dams is altered, and such abnor-
malities may represent a major underlying pathophysiology of
psychiatric disorders with a neurodevelopmental origin.
The LPS model used in this study does not fully recapitulate
the events triggered by bacterial pathogens and their toxins
in the foetal brain, and reproduces only part of the
inflammation-mediated effects. Nonetheless, our study has
set the stage to unravel the sequelae of events that underlie
the neurobehavioural deficits reported in animals exposed to
an antenatal insult.
We thank Donna Crandall for her help with the preparation
of the Figures, Catalina Abad for insightful discussions and
help with the ELISA assays, Elvira Khialeeva and Diane
Anthony for their help with the H&E staining, Justin Lam and
Linda L. Kalamkeryan for technical help. We are grateful to
Christopher S. Colwell and David E. Krantz for critically
reading the manuscript before submission.
N.S.M. was supported by an NINDS-Rita L. Kirschstein NRSA
Fellowship. This work was supported by a Pilot and Feasibility
grant from the UCLA Center for Neurobiology of Stress and a
Stein-Oppenheimer Award to J.d.V and C.A.G., a Semel Young
Investigator Award to C.A.G., and grants from the National
Institutes of Health [P01-HD06576 and HD04612] to J.d.V.
Ashdown H, Dumont Y, Ng M, Poole S, Boksa P, Luheshi GN (2006) The role
of cytokines in mediating effects of prenatal infection on the fetus:
implications for schizophrenia. Mol Psychiatry 11:47–55.
Bayer SA, Altman J (1991) Neocortical Development: Raven Press.
Bell MJ, Hallenbeck JM (2002) Effects of intrauterine inflammation on
developing rat brain. J Neurosci Res 70:570–579.
Bell MJ, Hallenbeck JM, Gallo V (2004) Determining the fetal inflammatory
response in an experimental model of intrauterine inflammation in rats.
Pediatr Res 56:541–546.
Berger-Sweeney J, Hohmann CF (1997) Behavioral consequences of abnormal
cortical development: insights into developmental disabilities. Behav
Brain Res 86:121–142.
Boksa P (2010) Effects of prenatal infection on brain development and
behavior: a review of findings from animal models. Brain Behav Immun
Brown AS (2006) Prenatal infection as a risk factor for schizophrenia.
Schizophr Bull 32:20 0–202.
Cameron HA, Hazel TG, McKay RD (1998) Regulation of neurogenesis by
growth factors and neurotransmitters. J Neurobiol 36:287–306.
Campbell K, Gotz M (2002) Radial glia: multi-purpose cells for vertebrate
brain development. Trends Neurosci 25:235–238.
Cui K, Ashdown H, Luheshi GN, Boksa P (2009) Effects of prenatal immune
activation on hippocampal neurogenesis in the rat. Schizophr Res
de Bergeyck V, Nakajima K, Lambert de Rouvroit C, Naerhuyzen B, Goffinet
AM, Miyata T, Ogawa M, Mikoshiba K (1997) A trun cated Reelin protein is
produced but not secreted in the ‘Orleans’ reeler mutation (Reln[rl-Orl]).
Brain Res Mol Brain Res 50:85–90.
Derer P, Derer M, Goffinet A (2001) Axonal secretion of Reelin by Cajal-
Retzius cells: evidence from comparison of normal and Reln(Orl) mutant
mice. J Comp Neurol 440:136–143.
Deutsch SI, Burket JA, Katz E (2010) Does subtle disturbance of neuronal
migration contribute to schizophrenia and other neurodevelopmental
disorders? Potentia l genetic mechanisms with possible treatment
implications. Eur Neuropsychopharmacol 20:281–287.
Deverman BE, Patterson PH (2009) Cytokines and CNS development. Neuron
Ellman LM, Susser ES (2009) The promise of epidemiologic studies: neuroimmune
mechanisms in the etiologies of brain disorders. Neuron 64:25–27.
Fatemi SH (2005) Reelin glycoprotein: structure, biology and roles in health
and disease. Mol Psychiatry 10:251–257.
Fatemi SH, Folsom TD (2009) The neurodevelopmental hypothesis of
schizophrenia, revisited. Schizophr Bull 35:528–548.
Forster E, Bock HH, Herz J, Chai X, Frotscher M, Zhao S (2010) Emerging
topics in Reelin function. Eur J Neurosci 31:1511–1518.
Ghiani CA, Gallo V (2001) Inhibition of cyclin E-cyclin-dependent kinase 2
complex formation and activity is associated with cell cycle arrest and
withdrawal in oligodendrocyte progenitor cells. J Neurosci 21:1274–1282.
Ghiani CA, Lelievre V, Beltran-Parrazal L, Sforza DM, Malvar J, Smith DJ,
Charles AC, Ferchmin PA, de Vellis J (2006) Gene expression is
differentially regulated by neurotransmit ters in embryonic neuronal
cortical culture. J Neurochem 97(Suppl 1):35–43.
Ghiani CA, Starcevic M, Rodriguez-Fernandez IA, Nazarian R, Cheli VT,
Chan LN, Malvar JS, de Vellis J, Sabatti C, Dell’Angelica EC (2010)
The dysbindin-containing complex (BLOC-1) in brain: developmental
regulation, interaction with SNARE proteins and role in neurite outgrowth.
Mol Psychiatry 15:115, 204–115.
Gupta A, Tsai LH, Wynshaw-Boris A (2002) Life is a journey: a genetic look at
neocortical development. Nat Rev Genet 3:342–355.
Hagberg H, Mallard C (2005) Effect of inflammation on central nervous
system development and vulnerability. Curr Opin Neurol 18:117–123.
Hartfuss E, Forster E, Bock HH, Hack MA, Leprince P, Luque JM, Herz J,
Frotscher M, Gotz M (2003) Reelin signaling directly affects radial glia
morphology and biochemical maturation. Development 130:4597–4609.
Herdegen T, Leah JD (1998) Inducible and constitutive transcription factors in
the mammalian nervous system: control of gene expressi on by Jun, Fos
and Krox, and CREB/ATF proteins. Brain Res Brain Res Rev 28:370–490.
Ignatova N, Sindic CJ, Goffinet AM (2004) Characterization of the various
forms of the Reelin protein in the cerebrospinal fluid of normal subjects
and in neurological diseases. Neurobiol Dis 15:326–330.
Jonakait GM (2007) The effects of maternal inflammation on neuronal
development: possible mechanisms. Int J Dev Neurosci 25:415–425.
Jossin Y, Ignatova N, Hiesberger T, Herz J, Lambert de Rouvroit C, Goffinet AM
(2004) The central fragment of Reelin, generated by proteolytic
processing in vivo, is critical to its function during cortical plate
development. J Neurosci 24:514–521.
Jossin Y, Gui L, Goffinet AM (2007) Processing of Reelin by embryonic
neurons is important for function in tissue but not in dissociated cultured
neurons. J Neurosci 27:4243–4252.
Juarranz Y, Abad C, Martinez C, Arranz A, Gutierrez-Canas I, Rosignoli F,
Gomariz RP, Leceta J (2005) Protective effect of vasoactive intestinal
peptide on bone destruction in the collagen-induced arthritis model of
rheumatoid arthritis. Arthritis Res Ther 7:R1034–R1045.
Kaufmann WE, Worley PF (1999) Neural activity and immediate early gene
expression in the cerebral cortex. Ment Retard Dev Disabil Res Rev 5:41–50.
Mattan NS, Ghiani CA, Lloyd M, Matalon R, Bok D, Casaccia P, de Vellis J
(2010) Aspartoacylase deficiency affects early postnatal development of
oligodendrocytes and myelination. Neurobiol Dis 40:432–443.
C.A. Ghiani and others
244 E 2011 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/)
which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.