Maternal thyroid hormone is required for parvalbumin neurone 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 hypothyroxinaemia, 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 α1 (TRα1). Consequently, mice heterozygous for a dominant-negative mutation in TRα1 display profound neuroanatomical abnormalities including deranged development of parvalbumin neurones. However, the exact timing and orchestration of TH signalling during parvalbumin neurone development remains elusive. In the present study, we dissect the development of parvalbumin neurones in the anterior hypothalamic area (AHA) in male mice using different mouse models with impaired pre- and postnatal TH signalling in combination with bromodeoxyuridine birth dating and immunohistochemistry. Our data reveal that hypothalamic parvalbumin neurones are born at embryonic day 12 and are first detected in the AHA at postnatal day 8, reaching their full population number at P13. Interestingly, they do not require TH postnatally because their development is not impaired in mice with impaired TH signalling after birth. By contrast, however, these neurones crucially depend on TH through TRα1 signalling in the second half of pregnancy, when the hormone is almost exclusively provided by the mother. For the first time, our findings directly link a maternal hormone to a neuroanatomical substrate in the foetal brain, and underline the importance of proper TH signalling during pregnancy for offspring mental health. Given the role of hypothalamic parvalbumin neurones in the central control of blood pressure, the present study advocates the inclusion of cardiovascular parameters in the current discussion on possible TH substitution in maternal hypothyroxinaemia.

A Pivotal Genetic Program Controlled by Thyroid Hormone during the Maturation of GABAergic Neurons

“…These results extend previous findings, obtained either in hypothyroid rodents or in mice with Thra mutations, demonstrating the role of TH in GABAergic neurons in the cerebellum (Fauquier et al, 2011;Manzano et al, 2007), striatum (Diez et al, 2008), cortex (Wallis et al, 2008), hippocampus (Navarro et al, 2015), and hypothalamus (Harder et al, 2018). The major contribution of the present work is to demonstrate that the effect of TH/TRa1 on GABAergic neuron development is cell-autonomous.…”

“…This allows TH to synchronize cellular interactions and the maturation of neuronal networks during the first post-natal weeks (Flamant et al, 2017). As defects in TH signaling are known to alter GABAergic neurons outside the cerebellum (Berbel et al, 1996;Harder et al, 2018;Wallis et al, 2008), we asked whether the direct role of TH in GABAergic neurons, initially observed in the cerebellum, could be generalized to other brain regions.…”

A pivotal genetic program controlled by thyroid hormone during the maturation of GABAergic neurons in mice

“…This suggests that, although GABAergic neurons of different brain areas have different embryonal origins (20,21), they share a common pathway of maturation that depends on TH/TRα1 signaling. These results extend previous findings on the role of TH in GABAergic neurons in the cerebellum (18,22), striatum (23), cortex (24), hippocampus (25) and hypothalamus (26). In many respects, neurodevelopmental damage caused by TRα1 L400R and TRα1 E395fs401X appears to be more dramatic than that reported for the TRα1 R384C mutation (24), which is impaired in its affinity for TH, but possesses a residual capacity to transactivate gene expression (27).…”

Critical Period Regulation by Thyroid Hormones: Potential Mechanisms and Sex-Specific Aspects

“…TH-mediated impairments in PV expression has been also found in the hippocampus of rats, an area extremely responsive to perinatal TH levels (Gould et al, 1990b; Gilbert et al, 2007; Sawano et al, 2013). Other brain regions where TH developmentally regulate PV expression include the hypothalamus (Harder et al, 2018) and the striatum (Bode et al, 2017). Given the importance of PV circuits in CP regulation, it is likely that perinatal TH deficits disrupt CP timing across brain regions, which can be adequately tested in sensory systems.…”