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

262 Citations (Scopus)

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

Fingerprint

Neurofibromin 1
gamma-Aminobutyric Acid
Learning
Synapsins
Long-Term Potentiation
GABA-A Receptor Antagonists
Phosphorylation
Neurons
Mutation
Neurofibromatosis 1
Learning Disorders
Hippocampus
Down-Regulation
Pharmacology

Keywords

  • MOLNEURO

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Cui, Y., Costa, R. M., Murphy, G. G., Elgersma, Y., Zhu, Y., Gutmann, D. H., ... 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

Neurofibromin Regulation of ERK Signaling Modulates GABA Release and Learning. / Cui, Yijun; Costa, Rui M.; Murphy, Geoffrey G.; Elgersma, Ype; Zhu, Yuan; Gutmann, David H.; Parada, Luis F.; Mody, Istvan; Silva, Alcino J.

In: Cell, Vol. 135, No. 3, 31.10.2008, p. 549-560.

Research output: Contribution to journalArticle

Cui, Y, Costa, RM, Murphy, GG, Elgersma, Y, Zhu, Y, Gutmann, DH, Parada, LF, Mody, I & Silva, AJ 2008, 'Neurofibromin Regulation of ERK Signaling Modulates GABA Release and Learning', Cell, vol. 135, no. 3, pp. 549-560. https://doi.org/10.1016/j.cell.2008.09.060
Cui Y, Costa RM, Murphy GG, Elgersma Y, Zhu Y, Gutmann DH et al. Neurofibromin Regulation of ERK Signaling Modulates GABA Release and Learning. Cell. 2008 Oct 31;135(3):549-560. https://doi.org/10.1016/j.cell.2008.09.060
Cui, Yijun ; Costa, Rui M. ; Murphy, Geoffrey G. ; Elgersma, Ype ; Zhu, Yuan ; Gutmann, David H. ; Parada, Luis F. ; Mody, Istvan ; Silva, Alcino J. / Neurofibromin Regulation of ERK Signaling Modulates GABA Release and Learning. In: Cell. 2008 ; Vol. 135, No. 3. pp. 549-560.
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