Levothyroxin replacement therapy restores hypothyroidism induced impairment of L-LTP induction: critical role of CREB.
Cyclic-AMP response element binding protein (CREB) is a transcription factor crucial for late phase long-term potentiation (L-LTP) induction and maintenance. Upon multiple high frequency stimulation (MHFS), large Ca(2+) influx activates adenylyl cyclase. This, in turn, activates PKA, which by itself or through MAPK p42/p44 can activate (phosphorylate) CREB. Upon phosphorylation, P-CREB activates multiple genes essential for L-LTP generation. Calcium calmodulin kinase IV (CaMKIV) is also activated by calcium and can directly activate CREB. We have shown previously that hypothyroidism impairs L-LTP and reduces the basal protein levels of CREB, MAPK p42/p44, and CaMKIV in area CA1 of the hippocampus. In the present study, levels of these signaling molecules were determined in area CA1 during the induction and maintenance phases of L-LTP. Standard MHFS was used to evoke L-LTP in the CA1 area of hypothyroid, levothyroxin treated hypothyroid and sham control anesthetized adult rats. Chronic levothyroxin treatment reversed hypothyroidism-induced L-LTP impairment. Five minutes after MHFS, western blotting showed an increase in the levels of P-CREB, and P-MAPK p42/p44 in sham-operated control, and levothyroxin treated hypothyroid animals, but not in hypothyroid animals. The protein levels of total CREB, total MAPK p42/p44, BDNF and CaMKIV were not altered in all groups five minutes after MHFS. Four hours after MHFS, the levels of P-CREB, and P-MAPK p42/p44 remained unchanged in hypothyroid animals, while they were elevated in sham-operated control, and levothyroxin treated hypothyroid animals. We conclude that respective normalized phosphorylation of essential kinases such as P-CREB and P-MAPK p42/p44 is correlated with restoration of normal L-LTP induction and maintenance in the CA1 area of levothyroxin-treated hypothyroid animals.
Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.
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Alzoubi
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA. Electronic address: kalkadhi@uh.edu.
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Alkadhi
D000818:Animals; D015153:Blotting, Western; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007037:Hypothyroidism / Q000150:complications / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013965:Thyroidectomy; D013974:Thyroxine / Q000494:pharmacology*
D017362:Cyclic AMP Response Element-Binding Protein; D013974:Thyroxine
CA1 area; ERK1/2; LTP; Rat; Thyroidectomy; Thyroxin