Thyroid Hormone Transporter Deficiency in Mice Impacts Multiple Stages of GABAergic Interneuron Development

Abstract

Cortical interneuron neurogenesis is strictly regulated and depends on the presence of thyroid hormone (TH). In particular, inhibitory interneurons expressing the calcium binding protein Parvalbumin are highly sensitive toward developmental hypothyroidism. Reduced numbers of Parvalbumin-positive interneurons are observed in mice due to the combined absence of the TH transporters Mct8 and Oatp1c1. To unravel if cortical Parvalbumin-positive interneurons depend on cell-autonomous action of Mct8/Oatp1c1, we compared Mct8/Oatp1c1 double knockout (dko) mice to conditional knockouts with abolished TH transporter expression in progenitors of Parvalbumin-positive interneurons. These conditional knockouts exhibited a transient delay in the appearance of Parvalbumin-positive interneurons in the early postnatal somatosensory cortex while cell numbers remained permanently reduced in Mct8/Oatp1c1 dko mice. Using fluorescence in situ hybridization on E12.5 embryonic brains, we detected reduced expression of sonic hedgehog signaling components in Mct8/Oatp1c1 dko embryos only. Moreover, we revealed spatially distinct expression patterns of both TH transporters at brain barriers at E12.5 by immunofluorescence. At later developmental stages, we uncovered a sequential expression of first Oatp1c1 in individual interneurons and then Mct8 in Parvalbumin-positive subtypes. Together, our results point to multiple cell-autonomous and noncell-autonomous mechanisms that depend on proper TH transport during cortical interneuron development.

TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice

“…It is well-established that TH controls cortical GABAergic interneuron development and regulates the expression of distinct calcium binding proteins such as parvalbumin [ 41 ]. Thus, not surprisingly Mct8/Oatp1c1 DKO mice exhibit an altered composition of the cortical GABAergic interneuron network with a highly reduced number of parvalbumin expressing neurons in several regions of the cerebral cortex [ 6 , 42 ]. Furthermore, patch-clamp recordings of cortical neurons revealed an increased frequency of spontaneous miniature inhibitory postsynaptic currents in brain slices of Mct8/Oatp1c1 DKO mice confirming disturbed inhibitory neuronal activity in Mct8/Oatp1c1 deficiency [ 43 ].…”

“…As a consequence, subsets of neurons may remain “TRIAC”-deficient and show therefore an impaired maturation including reduced dendritic outgrowth. Alternatively, the loss of grey matter volume might be explained by impaired TH transport processes during prenatal stages that in turn will compromise neurogenesis and neuronal migration as seen in other brain areas [ 42 , 45 ]. Furthermore, it is important to note that alterations in cell count and physical tissue volume do not necessarily correlate to grey matter volume changes assessed with VBM.…”

Maternal thyroid hormone increases neural cell diversity during zebrafish spinal cord neurodevelopment

“…In the developing mct8/octp1c1 double-KO embryonic mice cortex 36 , Hr and gad67 (respectively, homologs of zebrafish her2 and gad1b ) expressing cells are mostly lost dorsally, strongly suggesting that in all vertebrates studied so far, MT3 constitute an important factor in dorsal specification of neuron cell identities most notably inhibitory neuron development. In rat embryos, T3 deficiency decreases the proliferation and delays the maturation of the precursors of cerebellar GABAergic interneurons, with effects on the number of mature GABAergic neurons and GABAergic terminals 37, 38 . Notably, in mct8 morphants, it is observed a decrease in dorsal spinal cord neurons while is observed an increase in ventral motoneurons 13 .…”

An animal model for Pierpont syndrome: a mouse bearing the Tbl1xr1 Y446C/Y446C mutation

“…Subsequently, sections were dehydrated in rising concentrations of ethanol and air-dried. Third-generation fluorescence in situ hybridization (FISH) experiments were carried out as described previously ( 37 , 38 ). A probe against TRH consisting of a set of 20 individual sequences for the target was commercially designed and generated (Molecular Instruments).…”