Neurofibromin regulation of ERK signaling modulates GABA release and learning (Cell, 2008, 135:549-560)

報告日期: 2009/05/15
報告時間: 17:10/18:00
報告學生: 林宏國
講評老師: 許桂森

Neurofibromin regulation of ERK signaling modulates GABA release and learning

Yijun Cui, Rui M. Costa, Geoffrey G. Murphy, Ype Elgersma, Yuan Zhu, David H. Gutmann, Luis F. Parada, Istvan Mody, and Alcino J. Silva

CELL 135: 549–560, October 31, 2008


Speaker: Hong-Guo Lin (林宏國)

Commentator: Kuei-Sen, Hsu, Ph.D (許桂森 老師)

Date: 5/15 17:10 – 18:00



Previous studies have implicated ERK signaling in learning and long-term potentiation (LTP), a synaptic plasticity mechanism thought to underlie learning and memory. The signaling pathway includes a G-protein (Ras) working upstream of a core module consisting of three kinases. Neurofibromin, a Ras GPTase-activating protein (RasGAP) encoded by the neurofibromatosis type 1 (NF1) gene, is thought to modulate Ras/ERK signaling, LTP, and learning in mice. An Nf1 heterozygous null mutation (Nf1+/-) causes learning problems in mice and in human. However, how the increases in Ras/ERK signaling observed in the Nf1+/- mice led to changes in inhibition and deficits in LTP and learning is not be clarified. Therefore, the authors generate condition Nf1+/- mutant mice to test the spatial learning, and they find unexpected result suggesting a role for neurofibromin in inhibitory neurons. The further studies demonstrate that enhanced ERK and synapsin 1 phosphorylation of Nf1+/- mice result in increased GABA release in the hippocampus and the learning deficits are rescued by a subthreshold dose of GABAA antagonist. Importantly, the lasting increase in GABA release triggered by learning also indicates that the mechanisms uncovered here are of general importance for learning, and show that disruption of this mechanism accounts for the learning deficits in a mouse model of NF1.



1. Silva, A.J., Frankland, P.W., Marowitz, Z., Friedman, E., Lazlo, G., Cioffi, D., Jacks, T., and Bourtchuladze, R. A mouse model for the learning and memory deficits associated with neurofibromatosis type 1. Nat. Genent. 15, 1997

2. Costa, R.M., Federov, N.B., Kogan, J.H., Murphy, G.G., Stern, J., Ohno, M., Kucherlapati, R., Jacks, T., and Silva, A.J. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415, 2002