Developmental Hypothyroidism Increases the Expression of Kainate Receptors in the Hippocampus and the Sensitivity to Kainic Acid-Induced Seizures in the Rat

Thyroid hormones are essential for normal brain development, and multiple alterations at behavioral, cognitive, cellular, and molecular levels have been described in animals made hypothyroid during development. Here we analyzed the effect of developmental hypothyroidism in the rat on the sensitivity to kainic acid-induced limbic seizures and the expression of kainate receptors in the hippocampus. Our results show that hypothyroid rats are extremely sensitive to the proconvulsant and neurotoxic effects of kainic acid (KA). Hypothyroid rats entered in status epilepticus at a dose of KA three times lower than that required to reach status epilepticus in control animals. In accordance with this, high levels of glial activation and neuronal loss after low KA dose injections were observed only in the hippocampus of hypothyroid rats. These effects correlated with an increased expression of kainate receptor subunits, excluding GluR5, in the hippocampus of hypothyroid animals. The concentrations of GluR6, GluR7, KAR1, and KAR2 (ionotropic glutamate receptor subunits of the kainic acid subtype) mRNAs were increased between 50 and 250% in hypothyroid animals relative to the values in controls. In agreement with these results, Western blot and immunohistochemical analysis showed a clear increase in the hippocampal content of GluR6/7 proteins in hypothyroid animals. (Endocrinology 151: 3267-3276, 2010)