 When mice were created with this single, conservative amino acid substitution in TRβ, synaptic maturation and plasticity in the hippocampus was impaired almost as effectively as completely blocking thyroid hormone synthesis.This mechanism appears to be conserved in all mammals but not in TRα or any other nuclear receptors.Thus, phosphotyrosine-dependent association of TRβ with PI3K provides a potential mechanism for integrating regulation of development and metabolism by thyroid hormone and receptor tyrosine kinases.