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The Journal of Neuroscience, May 15, 2003, 23(10):4072-4080

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Focal Adhesion Kinase Is Required, But Not Sufficient, for the Induction of Long-Term Potentiation in Dentate Gyrus Neurons In Vivo

Ying C. Yang,¹ Yun L. Ma,² Shau K. Chen,² Cheng W. Wang,³ and Eminy H. Y. Lee²

¹Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan, ²Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, and ³Department of Zoology, National Taiwan University, Taipei 106, Taiwan, Republic of China

Tyrosine kinase phosphorylation plays an important role in the induction of long-term potentiation (LTP). Focal adhesion kinase (FAK) is a 125 kDa nonreceptor tyrosine kinase that shows decreased phosphorylation in fyn mutant mice, and Fyn plays a critical role in LTP induction. By examining the role of FAK involved in LTP induction in dentate gyrus in vivo with medial perforant path stimulation, we found that both FAK and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) phosphorylation were increased significantly 5 and 10 min after LTP induction, whereas cAMP-responsive element binding protein (CREB) phosphorylation was increased 40 min later. Transfection of the dominant-negative FAK mutant construct HA-FAK(Y397F) impaired LTP, whereas transfection of the constitutively activated form HA-FAK(1–100) reduced the threshold for LTP induction. Transfection of HA-FAK(1–100) by itself did not induce long-lasting potentiation. Further, transfection of the HA-FAK(Y397F) construct decreased FAK, MAPK/ERK, and CREB phosphorylation, and the inhibition of MAPK/ERK decreased CREB phosphorylation. Moreover, blockade of NMDA receptor (NMDAR) did not decrease FAK, MAPK/ERK, and CREB phosphorylation although LTP induction was blunted by NMDAR antagonist. These biochemical changes were not associated with low-frequency stimulation either. Immunoprecipitation results revealed that tyrosine phosphorylation of NR2A and NR2B as well as the association of phosphorylated FAK with NR2A and NR2B was increased with LTP induction. These results together suggest that FAK is required, but not sufficient, for the induction of LTP in a NMDAR-independent manner and that MAPK/ERK and CREB are the downstream events of FAK activation. Further, FAK may interact with NR2A and NR2B to modulate LTP induction.

Key words: focal adhesion kinase; long-term potentiation; mitogen-activated protein kinase/extracellular signal-regulated kinase; cAMP-responsive element binding protein; field EPSP; NMDA receptor; metabotropic glutamate receptor; phosphorylation

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Received Aug. 13, 2002; revised Feb. 19, 2003; accepted Feb. 24, 2003.

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