Prenatal Infection and Risk for Schizophrenia: IL-1β, IL-6, and TNFα Inhibit Cortical Neuron Dendrite Development

Abstract

Prenatal exposure to infection increases risk for schizophrenia, and we have hypothesized that inflammatory cytokines, generated in response to maternal infection, alter neuron development and increase risk for schizophrenia. We sought to study the effect of cytokines generated in response to infectionFinterleukin-1b (IL-1b), tumor necrosis factor-a (TNFa), and interleukin-6 (IL-6)Fon the dendritic development of cortical neurons. Primary mixed neuronal cultures were obtained from E18 rats and exposed to 0, 100, or 1000 units (U)/ml of IL-1b, TNFa, IL-6, or IL-1b þ TNFa for 44 h. MAP-2-positive neurons were randomly identified for each condition and the number of primary dendrites, nodes, and total dendrite length was determined. We found that 100 U of TNFa significantly reduced the number of nodes (27%, p ¼ 0.02) and total dendritic length (14%, p ¼ 0.04), but did not affect overall neuron survival. A measure of 100 U IL-1b þ TNFa significantly reduced the number of primary dendrites (17%, p ¼ 0.006), nodes (32%, p ¼ 0.001), and total dendritic length (30%, po0.0001), although it did not affect overall neuron survival. At 1000 U, each cytokine significantly reduced the number of primary dendrites (14-24%), nodes (28-37%), as well as total dendritic length (25-30%); neuron survival was reduced by 14-21%. These results indicate that inflammatory cytokines can significantly reduce dendrite development and complexity of developing cortical neurons, consistent with the neuropathology of schizophrenia. These findings also support the hypothesis that cytokines play a key mechanistic role in the link between prenatal exposure to infection and risk for schizophrenia.

Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling

“…38 In addition, the macrophage-specific overexpression of IL-10 also abolished the fetal brain TNF-a response to maternal immunological stimulation. TNF-a is known to have potent neurodevelopmental effects by inhibiting neuronal cell survival 11 and cortical dendrite development 12 and synergistic interactions exist between TNF-a and other proinflammatory cytokines in these processes. 12,39 Elevated fetal brain levels of TNF-a have also been implicated in the emergence of enhanced neuronal apoptosis in postnatal life.…”

“…TNF-a is known to have potent neurodevelopmental effects by inhibiting neuronal cell survival 11 and cortical dendrite development 12 and synergistic interactions exist between TNF-a and other proinflammatory cytokines in these processes. 12,39 Elevated fetal brain levels of TNF-a have also been implicated in the emergence of enhanced neuronal apoptosis in postnatal life. 17 Furthermore, increased maternal TNF-a levels during pregnancy have been directly associated with a higher incidence of postpubertal psychosis in the offspring.…”

“…This class of cytokines can modulate neuronal differentiation, 10 survival 11 and dendrite growth and complexity in vitro. 12 They may also be critically involved in the precipitation of the long-term behavioral, cognitive and pharmacological consequences of prenatal immune challenge as shown in vivo. [13][14][15][16][17][18][19][20] In contrast, very little is known about the putative roles of anti-inflammatory cytokines in the association between prenatal inflammation and the emergence of brain and behavioral abnormalities.…”

Biological risks for neurological abnormalities associated with hyperbilirubinemia

“…7,8 The cause of schizophrenia is unknown, but evidence suggests that this condition is associated with alterations in prefrontal connectivity involving glutamate transmission at NMDA receptors. 9 Most attractive is the suggested association between prenatal exposure to infection and the risk for schizophrenia, together with the role of cytokines in reducing dendrite development, 10 consistent with the neuropathology of schizophrenia. 11 Interestingly, we found that early exposure to UCB leads to impairment of neuronal development by reduction in the dendrite extension and ramification 12 and that this can possibly increase the risk for mental illness in later life.…”

Alteraciones metabólicas asociadas al uso de terapia antipsicótica

“…En pacientes esquizofrénicos se han evaluado los niveles de citokinas inflamatorias, encontrán-dose hasta la fecha resultados variables en los distintos estudios, pero en su mayoría muestran aumento de IL2, IL-6, ILß 1 y TNFα 46,47 . La medición de la proteína inflamatoria PCR también se ve elevada en estos pacientes, asociándose los niveles aumentados a mayor gravedad y compromiso psiquiátrico 48 .…”