Neurofibromin regulation of ERK signaling modulates GABA release and learning.
Cell
; 135(3): 549-60, 2008 Oct 31.
Article
em En
| MEDLINE
| ID: mdl-18984165
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 GABA(A) 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Genes da Neurofibromatose 1
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Potenciação de Longa Duração
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Neurofibromina 1
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MAP Quinases Reguladas por Sinal Extracelular
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Ácido gama-Aminobutírico
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Aprendizagem
Limite:
Animals
Idioma:
En
Revista:
Cell
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos