臨床上，合成性糖皮質類固醇dexamethasone（DEX）常被用來減低早產兒慢性呼吸系統疾病（Chronic lung disease）的發生。其主要作用係糖皮質類固醇可以促進界面活性蛋白（Surfactant protein）的合成及加速肺部的成熟。近年來的動物實驗及臨床觀察研究中卻發現，新生時期暴露在高劑量的類固醇藥物下，可能會影響其後神經功能的正常發育。然而，此理論之實驗論証及其可能的致因則仍然不是很清楚。因此，在此研究中我們設計一系列的實驗來證明此論點。我們的研究發現，大鼠在新生時期接受高劑量DEX投予下（模擬臨床上早產兒的使用劑量），會影響其發育時突觸後NMDA受體次單位的表現及改變海馬迴CA1區域的突觸神經塑性。在5週的大鼠，我們發現新生時期投予DEX會促進長期抑制現象（Long-term depression；LTD）的誘發；相反地，其長期增益現象（Long-term potentiation；LTP）的誘發則受到抑制。然而，這些差異在8週的大鼠並不明顯。此外，DEX對於長期抑制或是長期增益現象所造成的影響，主要係與海馬迴CA1神經元中Ca2+/calmodulin-dependent protein kinase II （CaMKII）Thr-286位置磷酸化程度表現增強以及protein phosphatase 1（PP1）活性的降低有關。我們也發現幼年時期接受DEX的老鼠，在接受壓力刺激時其血液中壓力荷爾蒙（corticosterone）的濃度明顯較控制組低，亦即對於壓力的感受性較差。另外藉由被動迴避試驗（Passive avoidance test）的結果也發現，在5週年齡DEX組的大鼠可觀察到其學習及記憶缺損的現象；而此等現象在大鼠8週時並不明顯。綜合此等結果，我們認為新生時期投予DEX會造成日後海馬迴CA1區域的突觸神經塑性改變，影響壓力感受的神經內分泌系統及干擾學習記憶的形成。然而，這些影響似乎只會表現在早期，而成熟後期則可以透過未知的作用方式修補恢復。

Synthetic glucocorticoid dexamethasone (DEX) is frequently used as a therapeutic agent to lessen the morbidity of chronic lung disease in premature infants. It was suggested that glucocorticoids could stimulate the production of surfactant-associated protein and lung maturation. Recently, more and more animal and clinical studies indicated that the early postnatal dexamethasone therapy might affect neurodevelopmental outcome. However little is known about the adverse neurodevelopmentaloutcome of this therapy. Here we show that a schedule of tapering doses of DEX similar to that used in premature infants altered NMDA receptor assembly in postsynaptic density（PSD）and changed the direction of hippocampal CA1 synaptic plasticity, favoring low-frequency stimulation-induced long-term depression (LTD) and opposing the induction of long-term potentiation (LTP) by high-frequency stimulation in adolescent (5-week-old) rats, but these alterations disappeared in young adult (8-week-old) rats. The effects of DEX on LTD and LTP were found to correlate with an increase in the autophosphorylation of Ca2+/calmodulin-dependent protein kinase II and a decrease in the protein phosphatase 1 activity. Furthermore, DEX-treated rats also demonstrated a blunted serum corticosterone response to a stress and exhibited disrupted memory retention in 5-week-old (but not 8-week-old) rats subjected to passive avoidance learning tasks. The association between behavioral test and hormonal stress responsiveness suggests that neonatal DEX treatment can alter the hippocampal synaptic plasticity, the neuroendocrine stress axis and the memory formation, but these impairments apparently are not permanent, which may be rescued through unidentified mechanisms.

Avery ME, Mead J（1959）Surface properties in relation to atelectasis and hyaline membrane disease. AMA J Dis Child 97:517-523.
Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M（1995）Immunosuppre ssion by glucocorticoid：inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 270:286-290.
Ballard PL, Ballard RA（1995） Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol 173:254-262.
Bashir ZI, Collingridge GL（1994）An investigation of depotentiation of long-term potentiation in the CA1 region of the hippocampus. Exp Brain Res 100:437-443.
Bear MF, Cooper LN, Ebner FF（1987） A physiological basis for a theory of synapse modification. Science 237:42-48.
Benke TA, Luthi A, Isaac JT, Collingridge GL（1998）Modulation of AMPA receptor unitary conductance by synaptic activity. Nature 393:793-797.
Bienenstock EL, Cooper LN, Munro PW（1982） Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. J Neurosci 2:32-48.
Bliss TV, Collingridge GL（1993） A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31-39
Braun AP, Schulman H (1995) A non-selective cation current activated via the multifunctional Ca2+-calmodulin-dependent protein kinase in human epithelial cells. J Physiol 488:37-55.
Burrin DG, Wester TJ, Davis TA, Fiorotto ML, Chang X（1999） Dexamethasone inhibits small intestinal growth via increased protein catabolism in neonatal pigs. Am J Physiol 276:E269-277.
Clark JC, Wert SE, Bachurski CJ, Stahlman MT, Stripp BR, Weaver TE, Whitsett JA（1995）Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice. Proc Natl Acad Sci USA 92:7794-7798.
Collingridge GL, Lester RA（1989）Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacol Rev 41:143-210.
De Kloet ER, Rosenfeld P, Van Eekelen JA, Sutanto W, Levine S（1988） Stress, glucocorticoids and development. Prog Brain Res 73:101-120.
De Kloet ER, Oitzl MS, Joels M.（1999） Stress and cognition: are
corticosteroids good or bad guys? Trends Neurosci 22:422-426.
Derkach V, Barria A, Soderling TR（1999） Ca2+/calmodulin-kinase II enhances channel conductance of AMPA receptors. Proc Natl Acad Sci USA 96:3269-3274
Devys D, Lutz Y, Rouyer N, Bellocq JP, Mandel JL（1993）The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nat Genet 4:335-340.
Dobbing J（1981） The later development of the brain and its vulnerability. In:Scientific Foundations of Paediatrics, edited by Davis JA. London:Heinemann, p. 744-759.
Dudek SM, Bear MF（1993） Bidirectional long-term modification of synaptic effectiveness in the adult and immature hippocampus. J Neurosci 13:2910-2918.
Emery DE, Larsson K（1979） Rat strain differences in copulatory behavior after para-chlorophenylalanine and hormone treatment. J Comp Physiol Psychol 93:1067-1084.
Flagel SB, Vazquez DM, Watson SJ Jr, and Neal CR Jr （2002） Effects of tapering neonatal dexamethasone on rat growth, neurodevelopment and stress response. Am J Physiol Regul Integr Comp Physiol 282:R55–R63.
Gold PE （1986） The use of avoidance training in studies of modulation of memory storage. Behav Neural Biol 46:87-98.
Gross I（1990）Regulation of fetal lung maturation. Am J Physiol 259:L337-344.
Hanson PI, Schulman H（1992）Neuronal Ca2+/calmodulin-dependent protein kinases. Annu Rev Biochem 61:559-560.
Hanson PI, Meyer T, Stryer L, Schulman H（1994） Dual role of calmodulin in auto-phosphorylation of multifunctional CaM kinase may underlie decoding of
calcium signals. Neuron 12:943-956.
Hsu KS, Huang CC, Liang YC, Wu HM, Chen YL, Lo SW, Ho WC（2002） Alterations in the balance of protein kinase and phosphatase activities and age-related impairments of synaptic transmission and long-term potentiation.
Hippocampus12:787-802.
Huang CC, Hsu KS（2006）Sustained activation of metabotropic glutamate receptor 5 and protein tyrosine phosphatases mediate the expression of DHPG-induced long-term depression in the hippocampal CA1 region. J Neurochem 96:179-194.
Huang CC, You JL, Wu MY, Hsu KS （2004） Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. J Biol Chem 279:12286-12292.
Huber KM, Kayser MS, Bear MF（2000）Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288:1254-1257.
Huber KM, Roder JC, Bear MF（2001）Chemical induction of mGluR5- and protein synthesis--dependent long-term depression in hippocampal area CA1. J
Neurophysiol 86:321-325.
Huber KM, Gallagher SM, Warren ST, Bear MF（2002）Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci 99:7746-7750.
Izquierdo I, Medina JH（1997） Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. Neurobiol Learn Mem 68:285-316.
Jacobson L, Sapolsky R（1991）The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev 12:118-134.
Kamphuis PJ, Gardoni F, Kamal A, Croiset G, Bakker JM, Cattabeni F, Gispen WH, van Bel F, Di Luca M, Wiegant VM（2003） Long-lasting effects of neonatal dexamethasone treatment on spatial learning and hippocampal synaptic plasticity: involvement of the NMDA receptor complex. FASEB J 17:911-913.
Kandel, E. R（2001）The molecular biology of memory storage: a dialog between genes and synapses. Science 294:1030–1038.
Katz LC, Shatz CJ (1996) Synaptic activity and the construction of cortical circuits. Science 274: 1133-1138.
Kaufman J, Plotsky PM, Nemeroff CB, Charney DS (2000) Effects of early adverse experiences on brain structure and function: clinical implications. Biol. Psychiatry 48:778–790.
Kim JJ, Yoon KS (1998) Stress: metaplastic effects in the hippocampus. Trends Neurosci 21: 505–509.
Kresch MJ, Gross I （1987）The biochemistry of fetal lung development. Clin Preinatol 14: 481-507.
Lee HK, Barbarosie M, Kameyama K, Bear MF, Huganir RL（2000） Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405:955-959.
Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ, Verter J, Temprosa M, Wright LL, Ehrenkranz RA, Fanaroff AA, Stark A, Carlo W, Tyson JE, Donovan EF, Shankaran S, Stevenson DK（2001）Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. Pediatrics 107:e1.
Liggins GC, Howie RN（1972）A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 50:515-525.
Liley HG, WhiRte RT, Warr RG, Benson BJ, Hawgood S, Ballard PL（1989）Regula-
tion of messenger RNAs for the hydrophobic surfactant proteins in human lung. J Clin Invest 83:1191-1197.
Linden DJ, Connor JA（1995）Long-term synaptic depression. Annu Rev Neurosci 18：319-357.
Lisman J, Schulman H, Cline H（2002）The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 3:175-190.
Liu D, Diorio J, Day JC, Francis DD, Meaney MJ (2000) Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nat Neurosci 3:799-806.
Malenka RC, Kauer JA, Perkel DJ, Mauk MD, Kelly PT, Nicoll RA, Waxham MN（1989）An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 340:554-557.
Malenka RC（1994）Synaptic plasticity in the hippocampus: LTP and LTD. Cell 78:535-538.
Mayford M, Wang J, Kandel ER, O'Dell TJ（1995） CaMKII regulates the frequency-response function of hippocampal synapses for the production of both LTD and LTP. Cell 81:891-904.
Mulkey RM, Endo S, Shenolikar S, Malenka RC（1994）Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 369:486-488.
Neal CR Jr, Weidemann G, Kabbaj M, Vazquez DM（2004）Effect of neonatal dexamethasone exposure on growth and neurological development in the adult rat. Am J Physiol Regul Integr Comp Physiol 287:R375-385.
Northway WH Jr, Rosan RC, Porter DY（1967）Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med 276:357-368.
O'Shea TM, Kothadia JM, Klinepeter KL, Goldstein DJ, Jackson BG, Weaver RG 3rd, Dillard RG（1999） Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics 104:15-21.
Pelkey KA, Askalan R, Paul S, Kalia LV, Nguyen TH, Pitcher GM, Salter MW, Lombroso PJ（2002） Tyrosine phosphatase STEP is a tonic brake on induction
of long-term potentiation. Neuron 34:127-138.
Poncer JC, Esteban JA, Malinow R（2002）Multiple mechanisms for the potentiation of AMPA receptor-mediated transmission by αCa2+/calmodulin-dependent protein kinase II. J Neurosci 22:4406-4411.
Raymond CR, Thompson VL, TateR WP, Abraham WC（2000）Metabotropic glutamate receptors trigger homosynaptic protein synthesis to prolong long-term potentiation. J Neurosci 20：969-976.
Reul JM, de Kloet ER （1986）Anatomical resolution of two types of
corticosterone receptor sites in rat brain with in vitro autoradiography and computerized image analysis. J Steroid Biochem 24:269-272.
Rittenhouse PA, Lopez-Rubalcava C, Stanwood GD, Lucki I（2002） Amplified behavioral and endocrine responses to forced swim stress in the Wistar-Kyoto rat. Psychoneuroendocrinology 27:303-318.
Rizvi ZB, Aniol HS, Myers TF, Zeller WP, Fisher SG, Anderson CL（1992）Effects of dexamethasone on the hypothalamic-pituitary-adrenal axis in preterm infants. J Pediatr 120:961-965.
Schoenfeld NM, Leathem JH, Rabii J（1980） Maturation of adrenal stress responsiveness in the rat. Neuroendocrinology 31：101-105.
Schwarz BE, Schultz FM, MacDonald PC, Johnston JM（1976）Initiation of human parturition. IV. Demonstration of phospholipase A2 in the lysosomes of human fetal membranes. Am J Obstet Gynecol 125:1089-1092.
Scoville WB, Milner B（1957）Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 20:11-21.
Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM（1988）Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 82:527-532.
Shields, S.M., Ingebritsen, T.S., and Kelly, P.T (1985). Identification of proteinphosphatase-1 in synaptic junctions—dephosphorylatonof endogenous CaMKII and synapse-enriched phosphoproteins. J. Neurosci 5:3414–3422.
Silva AJ, Wang Y, PaylRor R, Wehner JM, Stevens CF, Tonegawa S（1992）Alpha calcium/calmodulin kinase II mutant mice: deficient long-term potentiation and impaired spatial learnin Cold Spring Harb Symp Quant Biol 57:527-539.
Smith SL, Kirchhoff KT, Chan GM, Squire SJ（1994）Patterns of postnatal weight changes in infants with very low and extremely low birth weights. Heart Lung 23:439-445.
Snyder EM, Philpot BD, Huber KM, Dong X, Fallon JR, Bear MF（2001）Internalization of ionotropic glutamate receptors in response to mGluR activation. Nat Neurosci 4:1079-1085.
Speer CP（2001）New insights into the pathogenesis of pulmonary inflammation in preterm infants. Biol Neonate 79:205-209.
Suchecki D, Nelson DY, Van Oers H, Levine S（1995） Activation and inhibition of the hypothalamic-pituitary-adrenal axis of the neonatal rat: effects of maternal deprivation. Psychoneuroendocrinology 20：169-182.
Sweet DG., Halliday HL（1999） Current perspectives on drug treatment of neonatal respiratory distress syndrome. Paediatr Drug 1:19-30.
Todd PK, Malter JS（2002）Fragile X mental retardation protein in plasticity and disease. J Neurosci Res 70:623-630.
van der Heide-Jalving M, Kamphuis PJ, van der Laan MJ, Bakker JM, Wiegant VM,
Heijnen CJ, Veen S, van Bel F（2003）Short- and long-term effects of neonatal
glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone? Acta Paediatr 92：827-835.
Vyas J, Kotecha S（1997）Effects of antenatal and postnatal corticosteroids on the preterm lung. Arch Dis Child Fetal Neonatal Ed. 77:F147-150.
Watterberg KL, Gerdes JS, Gifford KL, Lin HM（1999）Prophylaxis against early
adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics 104:1258-1263.
Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S,
Szyf M, Meaney MJ（2004） Epigenetic programming by maternal behavior. Nat
Neurosci 7:847-854.
Wells DG, Dong X, Quinlan EM, Huang YS, Bear MF, Richter JD, Fallon JR（2001） A role for the cytoplasmic polyadenylation element in NMDA receptor-regulated mRNA translation in neurons. J Neurosci 21:9541-9548.
Wenthold Robert J., Petralia Ronald S., Jaroslav Blahos II, and Niedzielski Andrew S（1996） Evidence for multiple AMPA receptor complexes in
hippocampal CAl/CA2 neurons. The Journal of Neuroscience 76:1982-1989
Wiegert O, Joels M, Krugers H（2006）Timing is essential for rapid effects of corticosterone on synaptic potentiation in the mouse hippocampus. Learn Mem 13:110-113.
Woo NH, Nguyen PV（2003） Protein synthesis is required for synaptic immunity to depotentiation. J Neurosci 23:1125-1132.
Yang CH, Huang CC, Hsu KS（2004）Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellular signal-regulated kinase/mitogen-activated protein kinase activation. J Neurosci 24:11029-11034.
Yeh TF, Lin YJ, Lin HC, Huang CC, Hsieh WS, Lin CH, Tsai CH（2004）Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 350:1304-1313.
Zamanillo D, Sprengel R, Hvalby O, Jensen V, Burnashev N, Rozov A, Kaiser KM, Koster HJ, Borchardt T, Worley P, Lubke J, Frotscher M, Kelly PH, Sommer B, Andersen P, Seeburg PH, Sakmann B（1999） Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284:1805-1811.
Zhang LI, Poo MM (2001) Electrical activity and development of neural circuits. Nat Neurosci 4:1207-1214.
Zho WM, You JL, Huang CC, Hsu KS（2002） The group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine induces a novel form of depotentiation in the CA1 region of the hippocampus. J Neurosci 22:8838-8849.
Zucker RS（1989）Short-term synaptic plasticity. Annu Rev Neurosci 12:13-31.