Background: Subclinical hyperthyroidism is associated with cognitive impairment, but the mechanism has remained unclear. As subclinical hyperthyroidism is characterized by significantly decreased TSH levels, this study aimed to investigate whether TSH regulates cognitive function. Methods: The correlation between TSH and cognitive impairment was investigated in a cross-sectional population study. The role of TSH/TSH receptor (TSHR) signaling in spatial learning and memory was further examined

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... behavior tests in Tshr-/- mice. Dendritic spine, synaptic density and structure of hippocampal CA1 pyramidal neurons were detected by Golgi's method and electron microscopy. The mRNA and protein expression levels of learning and memory-related genes were assessed by RNA sequencing, real-time PCR, immunoblotting and immunofluorescence approaches. Results: Serum TSH level correlated negatively with cognitive impairment in the current population. Consistently, Tshr deletion in mice led to significantly compromised performance in hippocampus-dependent tasks, reduced dendritic spine density and excitatory synaptic density as well as altered synaptic structure in CA1 subfield of the hippocampus. Furthermore, the mRNA levels of learning and memory-related genes were altered, and protein levels of CREB-regulated genes were downregulated in the hippocampus of Tshr-/- mice. Conclusions: These findings reveal that TSH/TSHR signaling ablation impairs spatial learning and memory, indicating a decline in TSH level might contribute to the increased prevalence of cognitive impairment in subclinical hyperthyroidism patients.