Neurodevelopmental effects of chronic exposure to elevated levels of pro-inflammatory cytokines in a developing visual system

Ryan H. Lee, Elizabeth A. Mills, Neil Schwartz, Mark R. Bell, Katherine E. Deeg, Edward S. Ruthazer, Nicholas Marsh-Armstrong, Carlos D. Aizenman

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Background: Imbalances in the regulation of pro-inflammatory cytokines have been increasingly correlated with a number of severe and prevalent neurodevelopmental disorders, including autism spectrum disorder, schizophrenia and Down syndrome. Although several studies have shown that cytokines have potent effects on neural function, their role in neural development is still poorly understood. In this study, we investigated the link between abnormal cytokine levels and neural development using the Xenopus laevis tadpole visual system, a model frequently used to examine the anatomical and functional development of neural circuits.Results: Using a test for a visually guided behavior that requires normal visual system development, we examined the long-term effects of prolonged developmental exposure to three pro-inflammatory cytokines with known neural functions: interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α. We found that all cytokines affected the development of normal visually guided behavior. Neuroanatomical imaging of the visual projection showed that none of the cytokines caused any gross abnormalities in the anatomical organization of this projection, suggesting that they may be acting at the level of neuronal microcircuits. We further tested the effects of TNF-α on the electrophysiological properties of the retinotectal circuit and found that long-term developmental exposure to TNF-α resulted in enhanced spontaneous excitatory synaptic transmission in tectal neurons, increased AMPA/NMDA ratios of retinotectal synapses, and a decrease in the number of immature synapses containing only NMDA receptors, consistent with premature maturation and stabilization of these synapses. Local interconnectivity within the tectum also appeared to remain widespread, as shown by increased recurrent polysynaptic activity, and was similar to what is seen in more immature, less refined tectal circuits. TNF-α treatment also enhanced the overall growth of tectal cell dendrites. Finally, we found that TNF-α-reared tadpoles had increased susceptibility to pentylenetetrazol-induced seizures.Conclusions: Taken together our data are consistent with a model in which TNF-α causes premature stabilization of developing synapses within the tectum, therefore preventing normal refinement and synapse elimination that occurs during development, leading to increased local connectivity and epilepsy. This experimental model also provides an integrative approach to understanding the effects of cytokines on the development of neural circuits and may provide novel insights into the etiology underlying some neurodevelopmental disorders.

Original languageEnglish (US)
Article number2
JournalNeural Development
Volume5
Issue number1
DOIs
StatePublished - Jan 12 2010
Externally publishedYes

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Cytokines
Synapses
Tumor Necrosis Factor-alpha
Larva
Pentylenetetrazole
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Xenopus laevis
N-Methylaspartate
Dendrites
Down Syndrome
N-Methyl-D-Aspartate Receptors
Interleukin-1
Synaptic Transmission
Epilepsy
Interleukin-6
Schizophrenia
Seizures
Theoretical Models
Neurons
Growth

ASJC Scopus subject areas

  • Developmental Neuroscience

Cite this

Lee, R. H., Mills, E. A., Schwartz, N., Bell, M. R., Deeg, K. E., Ruthazer, E. S., ... Aizenman, C. D. (2010). Neurodevelopmental effects of chronic exposure to elevated levels of pro-inflammatory cytokines in a developing visual system. Neural Development, 5(1), [2]. https://doi.org/10.1186/1749-8104-5-2

Neurodevelopmental effects of chronic exposure to elevated levels of pro-inflammatory cytokines in a developing visual system. / Lee, Ryan H.; Mills, Elizabeth A.; Schwartz, Neil; Bell, Mark R.; Deeg, Katherine E.; Ruthazer, Edward S.; Marsh-Armstrong, Nicholas; Aizenman, Carlos D.

In: Neural Development, Vol. 5, No. 1, 2, 12.01.2010.

Research output: Contribution to journalArticle

Lee, Ryan H. ; Mills, Elizabeth A. ; Schwartz, Neil ; Bell, Mark R. ; Deeg, Katherine E. ; Ruthazer, Edward S. ; Marsh-Armstrong, Nicholas ; Aizenman, Carlos D. / Neurodevelopmental effects of chronic exposure to elevated levels of pro-inflammatory cytokines in a developing visual system. In: Neural Development. 2010 ; Vol. 5, No. 1.
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