We are investigating the consequences of PI3K signaling for the physiological effects of thyroid hormone on brain development. Our group has recently identified two tyrosines in the second zinc finger of the mammalian thyroid hormone receptor, TR beta, that are essential for stimulation of PI3K. When either tyrosine is mutated, PI3K stimulation by thyroid hormone is blocked without preventing the receptor from binding to canonical thyroid hormone response elements in DNA and stimulating transcription. To test the relative importance of direct gene regulation and PI3K stimulation in thyroid hormone action during brain development, we made a mutant knock-in strain of mice with a phenylalanine replacing one of these tyrosines, Y147F in TRbeta1 (Y161F in TRbeta2). We made whole-cell recordings under voltage-clamp from CA1 neurons in hippocampal slices from postnatal day 13-17 mice, and measured synaptic responses to stimulation of Schaffer collaterals. Synaptic plasticity in the mutants was disrupted. However, TRb expression in the neurons and TSHb expression in pituitary, which is fregulated by TRb through direct DNA binding, are both normal in the mutant. In summary, thyroid hormone signaling through PI3K appears to be essential for maturation of postnatal plasticity of both excitatory and inhibitory synapses on mouse hippocampal pyramidal neurons. In addition we have shown that thyroid hormone signaling through PI3K has acute effects on synaptic plasticity that are mediated presynaptically, and we have tested that hypothesis by rescuing potentiation in the mutant by infecting the presynaptic neurons with wild-type TRb. Thus, disruption of thyroid hormone signaling through PI3K by environmental toxicants could be an important mechanism for environmental effects on human cognitive development, and we have discovered that bisphenol A blocks this novel signaling pathway. We have also found effects of the mutation on neuronal excitability that matches changes in activity-dependent gene expression as determined by RNAseq. In collaboration with Dr. Sheryl Moy in the Dept. Psychiatry at UNC Chapel Hill, we are testing the effects of this mutation on the mice's behavior in classical learning and memory paradigms.
|Martin, Negin P; Marron Fernandez de Velasco, Ezequiel; Mizuno, Fengxia et al. (2014) A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TR?, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo. Endocrinology 155:3713-24|
|Sanchez-Ortiz, Efrain; Hahm, Byoung Kwon; Armstrong, David L et al. (2009) Protein phosphatase 5 protects neurons against amyloid-beta toxicity. J Neurochem 111:391-402|