出生前後的短期低鈣血症對海馬迴腦區中BDNF的表現以及學習與記憶活動的影響

早發性短暫的新生兒低鈣血症是臨床上常見的疾病，並且可能導致新生兒產生數種神經症狀，包括了震顫、肌肉乏力以及筋孿等現象，然而，過去對於新生兒低鈣血症是否會造成長期腦部神經發育的異常，無論在臨床上或是基礎研究中，鮮少有人進行謹慎的定義或是深入的探討。Brain-derived neurotrophic factor (BDNF) 是neurotrophin家族中的一員，過去的研究結果顯示BDNF在神經可塑性以及學習與記憶功能中是重要的調控因子，而BDNF蛋白質的製造，可以依賴鈣離子選擇性的流通過細胞膜上的NMDA receptor以及voltage-gated Ca2+ channels進入細胞內，改變細胞內鈣離子濃度來進行調控，因此細胞外鈣離子濃度的降低，可能會短暫的影響鈣離子流通進入細胞膜的量，使BDNF蛋白質的表現發生改變，並藉此更進一步的改變神經發育後期對學習與記憶能力的影響。而cAMP response element-binding (CREB)蛋白質是調節BDNF基因表現的訊息傳遞因子，過去有研究顯示鈣離子可能會透過磷酸化CREB蛋白質，進一步活化Bdnf gene的promoter來使下游基因進行轉錄作用製造mRNA，而影響BDNF蛋白質的合成與釋放。本篇研究中，我們利用懷孕母鼠在產前連續二天給予calcitonin皮下注射，使出生之小鼠產生暫時性的低鈣血症，在這個模式下，我們測量出生後小老鼠海馬迴內BDNF蛋白質與mRNA的量，並在老鼠出生後30天與出生後60天利用水迷宮實驗測量小老鼠學習與記憶的能力，結果顯示，在小鼠腦部海馬迴BDNF表現量，短暫低鈣血症的小老鼠呈現出短暫的BDNF mRNA降低，同時在身長與體重的發育速度表現較遲緩，測量海馬迴中蛋白質的量，結果顯示無論是BDNF蛋白質表現量或是調控其基因活性的上游轉錄因子p-CREB蛋白質表現量，都在出生後第一天小鼠身上表現較低的現象且無統計上的差異，但是在小鼠出生後第7天，短暫低鈣血症的小老鼠呈現出高於正常組別的表現量，表示出早期短暫的低鈣血症會影響海馬迴中上游轉錄因子，並進而影響BDNF蛋白質量的表現；在水迷宮實驗中，可以發現短暫低血鈣現象會改變出生後30天小老鼠的學習效率以及探索求生的行為模式，更有趣的現象是在老鼠求生時游泳的速度明顯低於正常組別，這樣的結果或許也與正常老鼠在壓力環境下求生存的能力有關。依據實驗結果得知，出生後短期低鈣血症可以短暫的影響海馬迴中BDNF的表現量，並更進一步影響後期的學習行為，這樣的影響是借由甚麼來引起的暫時還不得而知，未來要解釋這些現象還需要進行更深入的實驗以及探討。

關鍵字

低鈣血症； BDNF ；學習與記憶

並列摘要

Early transient neonatal hypocalcemia is a common disorder and could induce several neurological symptoms in newborn babies, including tremor, weakness, and seizure. However, the long-term sequels of hypocalcaemia in the developing brain have not been carefully characterized, both in clinics and research. Brain-derived neurotrophic factor (BDNF) is one of neurotrophin family. It was thought to play an important role in synaptic plasticity and learning and memory. The translation of BDNF protein is dependent on Ca2+ influx through NMDA receptors or voltage-gated Ca2+ channels, and was modulated by calcium-dependent signal pathway. It is possible that transient reduced extracellular calcium perinatally may interfere in the expression of BDNF and later development of learning and memory activity. The calcium-mediated BDNF expression may through the phosphorylation of CREB, which is a transcription factor taking a role in the molecular steps stabilize memory in the brain. Here, we used an animal modal to mimic the transient perinatal hypocalcemia. The result showed that the hypocalcemia- group rats had transient decrease in the expression of BDNF mRNA in the hippocampus during the first post-natal week with an apparent decrease in the weight gain and body length. There also showed a transient increase in the expression of BDNF and p-CREB in hypocalcemia-group at post-natal day 7. The water-maze study showed that hypocalcemia-group had significantly reduce in the exploration activity and speed in swimming, and learning progression as compared to that of control group rats at post-natal day 30. This result suggested that transient post-natal hypocalcemia could produce a transient effect on the hippocampal BDNF expression, and an effect on the learning behavior. The underling neuropathology of these two phenomenon is worthy for further elucidation.

並列關鍵字

hypocalcemia ； BDNF ； learning/memory

參考文獻

1 Giorgio Aicardi, Emanuela Argilli, Silvia Cappello, Spartaco Santi, Massimo Riccio, Hans Thoenen, and Marco Canossa, "Induction of Long-Term Potentiation and Depression Is Reflected by Corresponding Changes in Secretion of Endogenous Brain-Derived Neurotrophic Factor", Proc Natl Acad Sci U S A., November 2 (2004), 101(44): 15788–92.

2 T. Aid, A. Kazantseva, M. Piirsoo, K. Palm, and T. Timmusk, "Mouse and Rat Bdnf Gene Structure and Expression Revisited", J Neurosci Res, 85 (2007), 525-35.

3 Agnieszka Balkowiec, and David M. Katz, "Cellular Mechanisms Regulating Activity-Dependent Release of Native Brain-Derived Neurotrophic Factor from Hippocampal Neurons.", The Journal of Neuroscience, Dec 1 (2002), 10399-407.

4 Y. A. Barde, D. Edgar, and H. Thoenen, "Purification of a New Neurotrophic Factor from Mammalian Brain", EMBO J, 1 (1982), 549-53.

6 C. R. Bramham, and E. Messaoudi, "Bdnf Function in Adult Synaptic Plasticity: The Synaptic Consolidation Hypothesis", Prog Neurobiol, 76 (2005), 99-125.

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出生前後的短期低鈣血症對海馬迴腦區中BDNF的表現以及學習與記憶活動的影響

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