Histological, functional and transcriptomic alterations in the juvenile hippocampus in a mouse model of thyroid hormone resistance

Abstract

Background: Proper thyroid hormone signaling via the TRα1 nuclear receptor is required for normal neurodevelopmental processes. The specific downstream mechanisms mediated by TRα1 that impact brain development remain to be investigated. Methods: In this study, the structure, function, and transcriptome of hippocampal tissue in a mouse model expressing the first RTHα mutation discovered in a patient, THRAE403X, were analyzed. RNAscope was used to visualize the spatial and temporal expression of Thra1 mRNA in the hippocampus of wild-type mice, which corresponds to THRA1 mRNA in humans. The morphological structure was analyzed by Nissl staining, and the synaptic transmission was analyzed on the basis of long-term potentiation. The Morris water maze test and the zero maze test were used to evaluate the behavior. RNA-seq and quantitative real-time PCR were used to analyze the differentially expressed genes (DEGs) of the hippocampal tissues in the mouse model expressing the ThraE403X mutation. Results: The juvenile mutant ThraE403X mice presented with delayed neuronal migration, disordered neuronal distribution, and decreased synaptic plasticity. A total of 754 DEGs, including 361 upregulated genes and 393 downregulated genes, were identified by RNA-seq. DEG-enriched Gene Ontology (GO) and KEGG pathways were associated with PI3K−Akt signaling, ECM−receptor interaction, neuroactive ligand−receptor interaction, and a range of immune-related pathways. 25 DEGs were validated by qPCR. Conclusions: The ThraE403X mutation results in histological and functional abnormalities, as well as transcriptomic alterations in the juvenile mouse hippocampus. This study of the ThraE403X mutant offers new insights into the biological cause of RTHα-associated neurological diseases.

Microglial infiltration mediates cognitive dysfunction in rat models of hypothalamic obesity via a hypothalamic-hippocampal circuit involving the lateral hypothalamic area

“…Next, we detected inflammatory cells infiltrating the hippocampus in the two groups and found that compared with those in the sham-operated group, there were an increase in the hippocampal glial cells and the soma of Iba1 + cells in the HO group ( P < 0.01, Figure 5A ). Synaptic plasticity in the hippocampus is required for cognition ( Fang et al, 2022 ; Hösli et al, 2022 ); therefore, we evaluated the co-expression of the microglial and synaptic-related proteins, the presynaptic and postsynaptic markers synaptophysin (SYN) and postsynaptic density protein 95 (PSD95). The results showed increased SYN-immunoreactive and PSD95-immunoreactive materials inside the microglial, suggesting there was more engulfment of synaptic components in HO rats ( P < 0.05, Figures 5B,C ).…”

Thyroid hormone action during GABAergic neuron maturation: The quest for mechanisms

“…Several criteria should be fulfilled for a gene to be considered as a direct TR target gene. First, if one considers that TRs are essentially transcription activators, their target genes are expected to be down-regulated in the brain of hypothyroid mice or in the brain of mice carrying mutations that impair TH signaling ( 74 , 91 – 93 ). Gene expression analyses in a variety of mouse models with impaired thyroid hormone signaling have confirmed that TR KO mice have an attenuated phenotype compared to hypothyroid mice, which is in agreement with a potent role of unliganded TRs in the repression of gene expression ( 13 ).…”

“…By contrast, Pvalb mRNA levels were not affected in TRβ1 -/- mice, suggesting a predominant implication of TRα1 in mediating the effects of TH on PV expression ( 13 ). Finally, in Thra E403X/E403X mice, which express the first Thra mutation that was discovered in a patient, RNA-sequencing analysis has shown that genes such as Flywch2 , Pvalb , and Syt2 , which are preferentially expressed in PV-expressing neurons, were downregulated compared to control mice ( 93 ). As a conclusion, Pvalb expression is significantly reduced in mouse models with altered TH signaling, but up to now there is no convincing evidence that Pvalb is a direct target gene of TRs.…”

Eating Disorders: Causes, Symptoms, Diagnosis and Management

“…Electrolyte abnormalities are prevalent and must be assessed to rule out hyponatremia from excessive water consumption, hypokalemia from excessive purging, or hypocalcaemia and hypomagnesaemia from incorrect laxative usage. Thyroid function, as well as plasma ferritin, folate, and vitamin B12, should be evaluated (Ben-Zeev et al, 2022;D'Aurizio et al, 2022;Fang et al, 2022).…”