Congenital Hypothyroidism Dysregulates TRPC6 to Mediate Abnormal Dendritic Spine Growth of Hippocampal Neurons.

BACKGROUND: Congenital hypothyroidism (CH) may lead to irreversible neurological dysfunction of offspring by affecting hippocampal morphogenesis. The dentate gyrus (DG) is primarily the affected tissue by the CH, in which the dendritic spine density of gyrus granule cells (DGCs) is significantly reduced, thereby resulting in the cognitive impairment. The CaMKIV/CREB signaling pathway has been shown to mediate the deficient growth of DGCs dendritic spines, but the mechanism of CH in modulating the Ca(2+)-dependent CaMKIV is still elusive. METHODS: CH model of rat pups was prepared by the supply of 0.02% methimazole in the drinking water of pregnant dams from the 9th day of gestation. The dendritic spine density of hippocampal DGCs was detected by Golgi staining before or after administration of drugs. Additionally, the expression of CH-mediated effectors in the hippocampus or primary neurons was determined by Western blot or RT-PCR, and the immunofluorescence or subcellular fractionation was used to examine the distribution of these factors. RESULTS: In the present study, the calcium influx-related channel TRPC6 was identified under the regulation of T3, which was significantly downregulated in the DGCs of CH pups. TRPC6 deficiency has been revealed to decrease the dendritic spine density by affecting intracellular calcium transients and the CaMKIV/CREB signaling pathway. Pharmacological activation of TRPC6 with hyperforin was shown to be efficient in the rescue of DGCs dendritic spines and in improving the cognitive function of CH pups. CONCLUSIONS: CH of the neonates leads to downregulation of TRPC6 in hippocampal dentate gyrus neurons, which affects calcium influx and decreases activation of CaMKIV and downstream signaling, thereby causing abnormal growth of DGCs' dendritic spines and impaired cognitive function in the offspring. This study provides a new target for CH-mediated developmental abnormality of the hippocampus in the offspring.