Congenital hypothyroidism impairs spine growth of dentate granule cells by downregulation of CaMKIV

Qingying Tang,Jinlong Shi,Yongjun Wang,Youjia Wu,Honghua Song,Shuxia Chen,Hui Wu

doi:10.1038/s41420-021-00530-z

Abstract

Congenital hypothyroidism (CH), a common neonatal endocrine disorder, can result in cognitive deficits if delay in diagnose and treatment. Dentate gyrus (DG) is the severely affected subregion of the hippocampus by the CH, where the dentate granule cells (DGCs) reside in. However, how CH impairs the cognitive function via affecting DGCs and the underlying mechanisms are not fully elucidated. In the present study, the CH model of rat pups was successfully established, and the aberrant dendrite growth of the DGCs and the impaired cognitive behaviors were observed in the offspring. Transcriptome analysis of hippocampal tissues following rat CH successfully identified that calcium/calmodulin-dependent protein kinase IV (CaMKIV) was the prominent regulator involved in mediating deficient growth of DGC dendrites. CaMKIV was shown to be dynamically regulated in the DG subregion of the rats following drug-induced CH. Interference of CaMKIV expression in the primary DGCs significantly reduced the spine density of dendrites, while addition of T3 to the primary DGCs isolated from CH pups could facilitate the spine growth of dendrites. Insights into relevant mechanisms revealed that CH-mediated CaMKIV deficiency resulted in the significant decrease of phosphorylated CREB in DGCs, in association with the abnormality of dendrites. Our results have provided a distinct cell type in hippocampus that is affected by CH, which would be beneficial for the treatment of CH-induced cognitive deficiency.

Highlights

Congenital hypothyroidism (CH) is one of important pediatric health concerns, as it impacts on child growth and neurodevelopment if delay in early treatment [1, 2]
The results indicate that CH-induced deficiency of calmodulin-dependent protein kinase IV (CaMKIV) primarily affects spine aberrancy of dentate granule cells (DGCs) by inactivation of CREB in a transient and region-specific manner
CH is caused by thyroid dysgenesis or impaired thyroid-stimulating hormone (TSH)-mediated stimulation of the thyroid gland [1, 42]

Summary

INTRODUCTION

Congenital hypothyroidism (CH) is one of important pediatric health concerns, as it impacts on child growth and neurodevelopment if delay in early treatment [1, 2]. In the enrichment analysis classified these DEGs involved in the present study, we successfully established CH model of rat fetus biological process of anatomical structure morphogenesis, negaand investigated the CH effects on the cognitive function of the tive regulation of growth, developmental process, and response to animals. Subsequent transcriptome profile analysis time points, and characterized nine functional genes associated revealed that CaMKIV acted as a central hub responsible for CH- with important biological processes, including neuroactive mediated impairment of DGC dendrite growth during develop- ligand–receptor interaction following CH (Fig. 4A, B). To elucidate the mechanism of CH impairment on dendritic growth of hippocampal neurons, we performed inge-

RESULTS

DISCUSSION

MATERIALS AND METHODS

Findings

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