Thyroid hormone-dependent development of the GABAergic pre- and post-synaptic components in the rat hippocampus.
Thyroid hormone (TH) plays essential roles in normal brain development mainly by regulating gene expression through binding to specific nuclear receptors which serve as transcription factors. Previous studies showed that perinatal deficiency of TH or impairment of its signaling severely affect brain development, especially the development of the γ-aminobutyric acid (GABA) system, but cellular and molecular targets of the hormone are only partly uncovered. In the present study, we focused on the developing rat hippocampus which was confirmed to be one of the regions highly sensitive to TH status, and found two new targets of the hormone among the pre- and post-synaptic components of the GABAergic system. One was glutamic acid decarboxylase 65 (GAD65), the protein level of which was reduced to less than 50% of control in the hippocampus of hypothyroid rats (obtained by administering 0.025% methimazole in drinking water to pregnant dams from gestational day 15 until 4 weeks postpartum) and recovered to control levels by daily thyroxine-replacement after birth. Reduction in GAD65 protein was correlated immunohistochemically with a 37% reduction in the number of GAD65-positive cells as well as a reduction in GAD65-positive processes. In contrast, the other GAD isotype, GAD67, was not affected by TH status. A subpopulation of GABAergic neurons containing parvalbumin was also confirmed to be highly dependent on TH status. The second target of thyroid hormone was neuron-specific K(+)/Cl(-) co-transporter, KCC2, which is responsible for switching of GABA action from excitatory to inhibitory. In the euthyroid hippocampus, a sharp rise of kcc2 expression was observed at postnatal day (PND)10 which was followed by a large increase in KCC2 protein at PND15. This transient rise in kcc2 expression was completely suppressed by hypothyroidism, resulting in nearly 80% reduction in KCC2 protein at PND15. These results indicate that the development of GABAergic terminals and the excitatory to inhibitory maturation of GABA signaling are strongly dependent on TH.
Department of Chemistry and Biological Science, School of Science and Engineering, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chou-ku, Sagamihara, Kanagawa 252-5258, Japan. Electronic address: eri_1018_eri@hotmail.co.jp.
Erika
E
Sawano
Masaki
M
Takahashi
Takayuki
T
Negishi
Tomoko
T
Tashiro
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development*; D007037:Hypothyroidism / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000633:toxicity; D008297:Male; D010320:Parvalbumins / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D013963:Thyroid Hormones / Q000097:blood / Q000378:metabolism*; D013974:Thyroxine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000096922:K Cl- Cotransporters
D005968:Glutamate Decarboxylase; D007093:Imidazoles; D010320:Parvalbumins; D027981:Symporters; D013963:Thyroid Hormones; D013974:Thyroxine; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C107674:2-mercapto-1-methylimidazole; C401141:glutamate decarboxylase 2
Brain development; GABAergic system; GAD65; GAD67; Hippocampus; KCC2; Thyroid hormone