Maternal Thyroid Hormone is Required for Parvalbumin Neuron Development in the Anterior Hypothalamic Area

Abstract

Thyroid hormone (TH) is crucial for brain development and function. This becomes most evident in untreated congenital hypothyroidism, leading to irreversible mental retardation. Likewise, maternal hypothyroxinemia, a lack of TH during pregnancy, is associated with neurological dysfunction in the offspring such as autism and reduced intellectual capacity. In the brain, TH acts mainly through TH receptor alpha 1 (TRα1). Consequently, mice heterozygous for a dominant-negative mutation in TRα1 display profound neuroanatomical abnormalities including deranged development of parvalbumin neurons. However, the exact timing and orchestration of TH signaling during parvalbumin neuron development remains elusive. Here we dissect the development of parvalbumin neurons in the anterior hypothalamic area (AHA) in male mice using different mouse models with impaired pre- and postnatal TH signaling in combination with bromodeoxyuridine birth dating and immunohistochemistry. Our data reveal that hypothalamic parvalbumin neurons are born at embryonic day 12, are first detected in the AHA at postnatal day 8 and reach their full population number at P13. Interestingly, they do not require TH postnatally, as their development is not impaired in mice with impaired TH signaling after birth. In contrast, however, these neurons crucially depend on TH through TRα1 signaling in the second half of pregnancy - a period where the hormone is almost exclusively provided by the mother. Our findings therefore for the first time directly link a maternal hormone to a neuroanatomical substrate in the fetal brain, and underline the importance of proper TH signaling during pregnancy for offspring mental health. Given the role of hypothalamic parvalbumin neurons in the central control of blood pressure, the study advocates the inclusion of cardiovascular parameters in the current discussion on possible TH substitution in maternal hypothyroxinemia.

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