Kang Myoung-Goo, Guo Yurong, Huganir Richard L
Department of Neuroscience, The Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3549-54. doi: 10.1073/pnas.0812861106. Epub 2009 Feb 10.
AMPA receptors (AMPA-R) are major mediators of synaptic transmission and plasticity in the developing and adult central nervous system. Activity-dependent structural plasticity mediated by dynamic changes in the morphology of spines and dendrites is also essential for the formation and tuning of neuronal circuits. RhoA and Rac1 are known to play important roles in the regulation of spine and dendrite development in response to neuronal activity. These Rho GTPases are activated by guanine nucleotide exchange factors (GEFs). In this study, we identified GEF-H1/Lfc as a component of the AMPA-R complex in the brain. GEF-H1 is enriched in the postsynaptic density and is colocalized with GluR1 at spines. GEF-H1 activity negatively regulates spine density and length through a RhoA signaling cascade. In addition, AMPA-R-dependent changes in spine development are eliminated by down-regulation of GEF-H1. Altogether, these results strongly suggest that GEF-H1 is an important mediator of AMPA-R activity-dependent structural plasticity in neurons.
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPA受体）是发育中和成年中枢神经系统中突触传递和可塑性的主要介质。由棘突和树突形态的动态变化介导的活动依赖性结构可塑性对于神经元回路的形成和调节也至关重要。已知RhoA和Rac1在响应神经元活动调节棘突和树突发育中起重要作用。这些Rho鸟苷三磷酸酶由鸟嘌呤核苷酸交换因子（GEF）激活。在本研究中，我们鉴定出GEF-H1/Lfc是脑中AMPA受体复合物的一个组分。GEF-H1在突触后致密物中富集，并与棘突处的GluR1共定位。GEF-H1活性通过RhoA信号级联反应负向调节棘突密度和长度。此外，GEF-H1的下调消除了AMPA受体依赖性的棘突发育变化。总之，这些结果强烈表明GEF-H1是神经元中AMPA受体活性依赖性结构可塑性的重要介质。
