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Effects of Disrupting Calcium Homeostasis on Neuronal Maturation: Early Inhibition and Later Recovery

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Abstract

It has become increasingly clear that agents that disrupt calcium homeostasis may also be toxic to developing neurons. Using isolated primary neurons, we sought to understand the neurotoxicity of agents such as MK801 (which blocks ligand-gated calcium entry), BAPTA (which chelates intracellular calcium), and thapsigargin (TG; which inhibits the endoplasmic reticulum Ca2+-ATPase pump). Thus, E18 rat cortical neurons were grown for 1 day in vitro (DIV) and then exposed to vehicle (0.1% DMSO), MK801 (0.01–20 μM), BAPTA (0.1–20 μM), or TG (0.001–1 μM) for 24 h. We found that all three agents could profoundly influence early neuronal maturation (growth cone expansion, neurite length, neurite complexity), with the order of potency being MK801 < BAPTA < TG. We next asked if cultures exposed to these agents were able to re-establish their developmental program once the agent was removed. When we examined network maturity at 4 and 7 DIV, the order of recovery was MK801 > BAPTA > TG. Thus, mechanistically distinct ways of disrupting calcium homeostasis differentially influenced both short-term and long-term neuronal maturation. These observations suggest that agents that act by altering intracellular calcium and are used in obstetrics or neonatology may be quite harmful to the still-developing human brain.

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Acknowledgments

We are grateful for the technical support of Carla Lema Tomé. This work was supported by a Wake Forest University School of Medicine Faculty Development fund, a Mr and Mrs Tab Williams Jr and Family Neuroscience Research and Program Development Endowment, and NIH RO1 NS051632. Tissue culture procedures, imaging, and data analysis were performed by SLR, JA, EB, MA, and CPT. Manuscript and figures prepared by SLR, JA, and CPT. There are no conflicting interests for all authors.

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  1. Neurobiology & Anatomy, Wake Forest University Medical School, Medical Center Boulevard, Winston Salem, NC, 27157-1010, USA

    Sarah L. Ringler, Jamie Aye, Erica Byrne, Megan Anderson & Christopher P. Turner

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  1. Sarah L. Ringler
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  2. Jamie Aye
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  4. Megan Anderson
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  5. Christopher P. Turner
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Correspondence to Christopher P. Turner.

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Ringler, S.L., Aye, J., Byrne, E. et al. Effects of Disrupting Calcium Homeostasis on Neuronal Maturation: Early Inhibition and Later Recovery. Cell Mol Neurobiol 28, 389–409 (2008). https://doi.org/10.1007/s10571-007-9255-9

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  • DOI: https://doi.org/10.1007/s10571-007-9255-9

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