Enhanced neuronal loss under perinatal hypothyroidism involves impaired neurotrophic signaling and increased proteolysis of p75NTR

Recognition of the molecular events that lead to enhanced cell death is vital to understand the developmental cerebellar defects under hypothyroidism. Though neurotrophins promote the survival and development of neurons in the cerebellum, but the mechanism of their insufficiency mediated cell loss under hypothyroidism is unknown. Here in developmental hypothyroid rat model we report that hypothyroidism induced neuronal loss involve down regulation of neurotrophic survival signaling and increased truncation of the receptor p75NTR. Results showed that perinatal hypothyroidism besides repressing the expression of BDNF also impairs the maturation of NGF which results in decreased activation of ERK, CREB, NF-kappaB and AKT. Furthermore hypothyroidism caused an enhanced expression and proteolysis of p75NTR. The increased proteolysis of p75NTRin vivo and its association with death of granule neurons brings forward hitherto a p75NTR dependence signaling which along with compromised survival signaling could provide a neurotrophic basis of understanding the cause of enhanced cell death in developing cerebellum under hypothyroidism.