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Developmental thyroid hormone insufficiency and brain development: A role for brain-derived neurotrophic factor (BDNF)?*
Gilbert, M. AND S. Lasley. Developmental thyroid hormone insufficiency and brain development: A role for brain-derived neurotrophic factor (BDNF)?*. NEUROSCIENCE. Elsevier Science Ltd, New York, NY, 239:253-70, (2013).
Adverse outcome pathways (AOPs) describe biologic pathways that, when sufficiently perturbed, can lead to adverse health outcomes. Thyroid hormone (TH) regulates gene expression during critical periods of development in a number of organ systems, but most particularly the brain. Brain derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors, has been implicated in a host of brain functions including neuronal cell survival, neurite outgrowth, cell migration, regulation of excitatory-inhibitory balance, and glutamate-dependent dendritic growth, synapse formation, stabilization and plasticity, many of the effects associated with developmental TH insufficiency. In view of the importance of BDNF in these various roles, and because TH is clearly required for normal brain development, a number of laboratories have examined the potential relationship between TH and neurotrophin expression in developing brains. We propose that TH-mediated regulation of neurotrophins may represent an AOP underlying some of the persistent neurological impairments associated with developmental hypothyroidism. This manuscript reviews the available literature on neurotrophins and TH. The results using hypothyroid models have varied from declines, to no significant alteration, to BDNF induction. The impact of TH deprivation on BDNF is clearly age- and region-specific, however, with only a few exceptions, inquiry has been limited to severe hypothyroid models. Limited data are available for BDNF in animal models of moderate TH insufficiency that are unencumbered by confounds of general developmental delays, concerns for undernutrition, severe growth impairments, and excessive pup mortality. Because of these limitations, the available data shed little light on the kinds of TH disruption one sees with environmental contaminants. A more consistent pattern of effects was seen for a related neurotrophin, nerve growth factor (NGF) under conditions of TH-insufficiency. Future work using models of moderate TH insufficiency, examining dose-response relationships, with concurrent gene and protein determinations over a broad developmental time window that encompasses the fetal period will serve to elucidate the relationship between TH and neurotrophins. Furthermore, because BDNF involvement in network circuit formation and synaptic plasticity is rapidly regulated by neuronal activation, the role of BDNF in TH- mediated neuronal development and function may be more evident when studied under conditions of BDNF induction in response to synaptic activation, plasticity, enrichment, or injury. Examination of members of the neurotrophin family linked to low level TH disruption using models of moderate TH insufficiency are needed to evaluate the utility of neurotrophins as potential biomarkers of TH effects in brain and to elucidate this AOP.
Thyroid hormones (TH) are essential for normal brain development. Even subclinical hypothyroidism experienced in utero can result in neuropsychological deficits in children despite normal thyroid status at birth. Neurotrophins have been implicated in a host of brain cellular functions, and in particular, brain-derived neurotrophic factor (BDNF) has a well documented role in development and function of the nervous system. A number of laboratories have reported the effects of TH administration or severe deprivation on neurotrophin expression. This review provides an overview and update of recent developments in the thyroid field as they relate to the nervous system. Secondly, we describe an animal model of low level TH insufficiency that is more relevant to study the neurological consequences associated with the modest TH perturbations of subclinical hypothyroidism, or that would be anticipated from environmental contaminants with a mode-of-action that involves the thyroid. Finally, we review the available vivo literature on TH-mediated alterations in neurotrophins, particularly BDNF, and discuss their possible contribution to brain impairments associated with TH insufficiency. We conclude that consensus is not evident. The observations of BDNF protein and gene expression have varied as a function of hypothyroid model, age, and brain region. Only a handful of studies have investigated the relationship of neurotrophins and TH using models of TH deprivation that are not severe, and dose-response information is sparse. Differences in the models used, species, doses, regions assessed, age at assessment, and method employed to determine differences contribute to the difficulty in reaching a consensus. As such, the case for a direct role for BDNF in thyroid-mediated effects in brain based on the available literature is not compelling. We conclude that delineation of the potential role of neurotophins in TH-mediated neuronal development may be more fruitful by examining additional growth factors (e.g., nerve growth factor), moderate degrees of TH insufficiency, and younger ages. We further suggest that investigation of BDNF invoked by synaptic activation (ie. plasticity, enrichment, trauma) may serve to elucidate a role of thyroid hormone in BDNF-regulated synaptic function.