Effects of a rat model of gestational hypothyroidism on forebrain dopaminergic, GABAergic, and serotonergic systems and related behaviors

Abstract

Abstract We investigated the effects of maternal hypothyroidism on forebrain dopaminergic, GABAergic, and serotonergic systems and related behavior in adult rat offspring. Experimental gestational hypothyroidism (EGH) was induced by administering 0.02% methimazole (MMI) to pregnant rats from gestational day 9 to delivery. Neurotransmitter‐related protein and gene expression were evaluated in offspring forebrain at postnatal day (P) 120. Exploratory behavior, contextual fear conditioning, locomotion, and 30‐day reserpine Parkinson induction were assessed from P75‐P120. Protein and gene expression assessments of medial prefrontal cortex showed group differences in dopaminergic, GABAergic, and serotonergic receptors, catabolic enzymes, and transporters. Striatum of MMI offspring showed an isolated decrease in the dopaminergic enzyme, tyrosine hydroxylase. MMI exposure increased GABA and dopamine receptor expression in amygdala. MMI offspring also had decreased state anxiety and poor contextual fear conditioning. We found that baseline locomotion was not changed, but reserpine treatment significantly reduced locomotion only in MMI offspring. Our results indicated that restriction of maternal thyroid hormones reduced dopaminergic, GABAergic, and serotoninergic forebrain components in offspring. Tyrosine hydroxylase deficiency in the striatum may underlie enhanced reserpine induction of Parkinson‐like movement in these same offspring. Deficits across different neurotransmitter systems in medial prefrontal cortex and amygdala may underlie decreased state anxiety‐like behavior and reduced fear conditioning in offspring, but no changes in trait anxiety‐like behavior occurred with maternal MMI exposure. These findings strongly support the hypothesis that adequate delivery of maternal thyroid hormones to the fetus is crucial to the development of the central nervous system critical for emotion and motor regulation.