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Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus.

ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by autoantibodies and preferentially affecting women of childbearing age. Because the offspring of mothers with SLE show a high frequency of learning disorders, we hypothesized that maternally transferred autoantibodies that bind DNA and the N-methyl-D-aspartate receptor (NMDAR) could have a pathogenic role during fetal brain development. Here we describe a maternal SLE mouse model wherein pregnant dams harbored DNA-specific, NMDAR-specific autoantibodies throughout gestation. High titers of these autoantibodies in maternal circulation led to histological abnormalities in fetal brain and subsequent cognitive impairments in adult offspring. These data support a paradigm in which in utero exposure to neurotoxic autoantibodies causes abnormal brain development with long-term consequences. This paradigm may apply to multiple congenital neuropsychiatric disorders.

SUBMITTER: Lee JY

PROVIDER: S-EPMC2615794 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus.

Lee Ji Y JY Huerta Patricio T PT Zhang Jie J Kowal Czeslawa C Bertini Eva E Volpe Bruce T BT Diamond Betty B

Nature medicine 20081214 1

Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by autoantibodies and preferentially affecting women of childbearing age. Because the offspring of mothers with SLE show a high frequency of learning disorders, we hypothesized that maternally transferred autoantibodies that bind DNA and the N-methyl-D-aspartate receptor (NMDAR) could have a pathogenic role during fetal brain development. Here we describe a maternal SLE mouse model wherein pregnant dams harbored DNA-specific, N ...[more]

PMID: 19079257

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Project description:BackgroundImpairment of specific cognitive domains in schizophrenia has been associated with prefrontal cortex (PFC) catecholaminergic deficits. Among other factors, prenatal exposure to infections represents an environmental risk factor for schizophrenia development in adulthood. However, it remains largely unknown whether the prenatal infection-induced changes in the brain may be associated with concrete switches in a particular neurochemical circuit, and therefore, if they could alter behavioral functions.MethodsIn vitro and in vivo neurochemical evaluation of the PFC catecholaminergic systems was performed in offspring from mice undergoing maternal immune activation (MIA). The cognitive status was also evaluated. Prenatal viral infection was mimicked by polyriboinosinic-polyribocytidylic acid (poly(I:C)) administration to pregnant dams (7.5 mg/kg i.p., gestational day 9.5) and consequences were evaluated in adult offspring.ResultsMIA-treated offspring showed disrupted recognition memory in the novel object recognition task (t = 2.30, p = 0.031). This poly(I:C)-based group displayed decreased extracellular dopamine (DA) concentrations compared to controls (t = 3.17, p = 0.0068). Potassium-evoked release of DA and noradrenaline (NA) were impaired in the poly(I:C) group (DA: Ft[10,90] = 43.33, p < 0.0001; Ftr[1,90] = 1.224, p = 0.2972; Fi[10,90] = 5.916, p < 0.0001; n = 11); (NA: Ft[10,90] = 36.27, p < 0.0001; Ftr[1,90] = 1.841, p = 0.208; Fi[10,90] = 8.686, p < 0.0001; n = 11). In the same way, amphetamine-evoked release of DA and NA were also impaired in the poly(I:C) group (DA: Ft[8,328] = 22.01, p < 0.0001; Ftr[1,328] = 4.507, p = 0.040; Fi[8,328] = 2.319, p = 0.020; n = 43); (NA: Ft[8,328] = 52.07; p < 0.0001; Ftr[1,328] = 4.322; p = 0.044; Fi[8,398] = 5.727; p < 0.0001; n = 43). This catecholamine imbalance was accompanied by increased dopamine D1 and D2 receptor expression (t = 2.64, p = 0.011 and t = 3.55, p = 0.0009; respectively), whereas tyrosine hydroxylase, DA and NA tissue content, DA and NA transporter (DAT/NET) expression and function were unaltered.ConclusionsMIA induces in offspring a presynaptic catecholaminergic hypofunction in PFC with cognitive impairment. This poly(I:C)-based model reproduces catecholamine phenotypes reported in schizophrenia and represents an opportunity for the study of cognitive impairment associated to this disorder.

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Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus.

Publications

Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus.

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