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д·âÃæÐÅÓÐһЩ½²¾¿£¬Ð´µÄ²»ºÃ£¬ÎÄÕÂÂíÉϾ͸øÄãÍ˻ء£ ¾ÙÀýÒ»£¬ÕâÊÇһƪÎÒÃÇʵÑéÊÒÔÚNature Neuroscience·¢±íµÄÎÄÕ£¬ËüÊÇÕâÑùдµÄ£º We would like to submit the enclosed manuscript entitled "GDNF Acutely Modulates Neuronal Excitability and A-type Potassium Channels in Midbrain Dopaminergic Neurons", which we wish to be considered for publication in Nature Neuroscience ¡£½ÓÏÂÀ´Ëµ£¬ÎªÊ²Ã´Õâ¸öÎÄÕÂÊÇÖØÒªµÄ£¬GDNF has long been thought to be a potent neurotrophic factor for the survival of midbrain dopaminergic neurons, ÕâÊÇÈ˼ҹýÈ¥ÒѾ­·¢Ïֵģ¬Éñ¾­ÓªÑøÒò×ÓÒ»Ö±ÊDZ»ÈÏΪ¶ÔÖÐÄÔ¶à°Í°·Éñ¾­Ôª´æ»îÆð´Ù½ø×÷Ó㬽Ó×Å˵£¬which are degenerated in Parkinson¡¯s disease. ÈκοÆÑ§·¢ÏÖ£¬¼ÙÈç¸ú¼²²¡ÓйصϰÄǾÍÊǺÜÖØÒªµÄ£¬GDNFÒ»°ãÊǵ÷¿ØÖÐÄÔÉñ¾­Ï¸°ûµÄ´æ»î£¬In this paper, we report an unexpected, acute effect of GDNF on A-type potassium channels, leading to a potentiation of neuronal excitability, in the dopaminergic neurons in culture as well as in adult brain slices. Further, we show that GDNF regulates the K+ channels through a mechanism that involves activation of MAP kinase. Thus, this study has revealed, for the first time, an acute modulation of ion channels by GDNF. ÕâÒ»¶Î½²µÄÊÇÖ÷Òª·¢ÏÖ£¬½ÓÏÂÀ´ÎÒ½²ÎªÊ²Ã´ÊÇÖØÒªµÄ¡£Our findings challenge the classic view of GDNF as a long-term survival factor for midbrain dopaminergic neurons, ½Ì¿ÎÊéÉÏ˵GDNF survival factorÏÖÔÚÎÒÃÇÀ´ÌôÕ½Õâ¸ö´«Í³¹ÛÄÈçÓеÀÀí½«¸Äд½Ì¿ÆÊ飬ºÜÖØÒª¡£ÎÒÓÖ˵Õâ¸ö¹¤×÷suggest that the normal function of GDNF is to regulate neuronal excitability, and consequently dopamine release. ÕâÊÇÁíÍâÒ»¸öÖØÒªµÄ¹±Ïס£ °Í½ðÉ­ÊÏÖ¢Ö÷ÒªÊÇÒòΪÉñ¾­µÝÖʶà°Í°·µÄÊÍ·ÅϽµ£¬ÎÒÃÇ¿ÉÒÔͨ¹ýµ÷¿ØÉñ¾­ÐË·ÜÐÔ£¬À´µ÷¿Ø¶à°Í°·µÄÊÍ·Å¡£ These results may also have implications in the treatment of Parkinson¡¯s disease. ËùÒÔÕâÏ×÷Ò²ÓÐÁÙ´²ÒâÒå¡£½ÓÏÂÀ´Êǽ¨Ò飺Due to a direct competition and conflict of interest, we request that Drs. XXX of #1 Univ., and YY of #2 Univ. not be considered as reviewers. ÕâЩ½¨ÒéҲҪʵÊÂÇóÊÇ£¬ÕæÊǾõµÃÕâЩÈËÊÇÔÚ×öÀàËÆµÄ¹¤×÷£¬ÓоºÕù¡£

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¾ÙÀý¶þ£¬We would like to submit the enclosed manuscript entitled "Ca2£«-binding protein frequenin mediates GDNF-induced potentiation of Ca2£« channels and transmitter release", which we wish to be considered for publication in Neuron. We believe that two aspects of this manuscript will make it interesting to general readers of Neuron. First, we report that GDNF has a long-term regulatory effect on neurotransmitter release at the neuromuscular synapses. This provides the first physiological evidence for a role of this new family of neurotrophic factors in functional synaptic transmission. Second, we show that the GDNF effect is mediated by enhancing the expression of the Ca2£«-binding protein frequenin. Further, GDNF and frequenin facilitate synaptic transmission by enhancing Ca2£« channel activity, leading to an enhancement of Ca2£« influx. ¾ßÌå¿ÆÑ§ÄÚÈݲ»¶®Ã»ÓйØÏµ£¬ÖØÒªµÄÊÇÓÐûÓÐдÇå³þÒâÒå¡£Thus, this study has identified, for the first time, a molecular target that mediates the long-term, synaptic action of a neurotrophic factor. Our findings may also have general implications in the cell biology of neurotransmitter release. ÄãÐèÒªÖ¸³öÕâÊǵÚÒ»¡£ÕâÊÇÒ»¸ö´ó¼Ò¹ØÐĵÄÎÊÌ⣬¶øÇÒÊǵÚÒ»´Î±¨µÀµÄз¢ÏÖ£¬ÕâÑù²Å»á±»ÖØÊÓ¡£

   

¾ÙÀýÈý£¬ÊÇ1996Äê·¢±íÔÚNatureÉϵÄÎÄÕ¡£µ±Ê±ÎÒ¾õµÃ·ÖÁ¿»¹²»¹»£¬ËùÒÔ·âÃæÐÅÉϾÍдµÃ¶àÒ»µã¡£ Enclosed are copies of a manuscript entitled "BDNF and NT-4/5 Promote the Development of Long-Term Potentiation in the Hippocampus", which we wish to be considered for publication in Nature. As you know, there is a great deal of interest and excitement recently in understanding the role of neurotrophins in synapse development and plasticity. ÖÚËùÖÜÖª£¬ÕâÊÇÒ»¸ö´ó¼Ò¶¼¸ÐÐËȤµÄÎÊÌâ¡£Our manuscript provides, for the first time, the physiological evidence that neurotrophins regulate long-term potentiation (LTP).  The main point of the paper is that the neurotrophins BDNF and NT-4 induce an earlier appearance of LTP in developing hippocampus.   In contrast to recent Science article by XX group, È˼ҸոÕÔÚScienceÔÓÖ¾ÉÏ·¢±íµÄһƪÎÄÕ¡£We did not see that BDNF enhance basal synaptic transmission in adult hippocampus. NatureºÍScienceÏ໥¶¼Òª¾ºÕùµÄ£¬Èç¹û˵ÊÇScienceÉÏ·¢±íµÄÎÄÕÂÊÇ´íµÄ£¬Ò»¶¨»áÒýÆðÐËȤ¡£However, we found that in adult hippocampus, inhibition of BDNF/TrkB activity attenuated LTP, and weak tetanus that normally cannot induce LTP produced enduring LTP. ÕâÊÇÎÒÃǵķ¢ÏÖ¡£These findings may have implications in the basic mechanism for regulation of synapse development and long-term modulation of synaptic efficacy. ÕâÊÇÎÒÃÇÕâÏ×÷µÄÒâÒå¡£

Because of the rather competitive nature of the field and the important implication of our findings, we have not yet presented this work in any public forum. ÎÒÃÇÔÚ¹«¹²³¡ºÏûÓн²¹ýÕâ¸öÎÊÌâ¡£ However, confidential discussion with several prominent neuroscientists such as 111 and 222 have generated tremendous excitement.˽ÏÂÎÒÃÇÒѾ­¸øÒ»Ð©ÓÐÃûµÄר¼Ò¿´ÁËÎÒÃǵŤ×÷£¬ËûÃǶ¼¸Ðµ½ºÜÓÐÒâ˼,Ôö¼ÓÁË·ÖÁ¿¡£Thus, we feel that this work is of general interest and is suitable for publication in Nature¡£

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