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, Alcino J. Silva

Research output: Contribution to journalArticle

276 Scopus citations

Abstract

We uncovered a role for ERK signaling in GABA release, long-term potentiation (LTP), and learning, and show that disruption of this mechanism accounts for the learning deficits in a mouse model for learning disabilities in neurofibromatosis type I (NF1). Our results demonstrate that neurofibromin modulates ERK/synapsin I-dependent GABA release, which in turn modulates hippocampal LTP and learning. An Nf1 heterozygous null mutation, which results in enhanced ERK and synapsin I phosphorylation, increased GABA release in the hippocampus, and this was reversed by pharmacological downregulation of ERK signaling. Importantly, the learning deficits associated with the Nf1 mutation were rescued by a subthreshold dose of a GABAA antagonist. Accordingly, Cre deletions of Nf1 showed that only those deletions involving inhibitory neurons caused hippocampal inhibition, LTP, and learning abnormalities. Importantly, our results also revealed lasting increases in GABA release triggered by learning, indicating that the mechanisms uncovered here are of general importance for learning.

Original languageEnglish
Pages (from-to)549-560
Number of pages12
JournalCell
Volume135
Issue number3
DOIs
StatePublished - Oct 31 2008

Keywords

  • MOLNEURO

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    Cui, Y., Costa, R. M., Murphy, G. G., Elgersma, Y., Zhu, Y., Gutmann, D. H., Parada, L. F., Mody, I., & Silva, A. J. (2008). Neurofibromin Regulation of ERK Signaling Modulates GABA Release and Learning. Cell, 135(3), 549-560. https://doi.org/10.1016/j.cell.2008.09.060