Neurofibromin regulation of ERK signaling modulates GABA release and learning.
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.
Cui
Yijun
Y
Department of Neurobiology, Brain Research Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Costa
Rui M
RM
Murphy
Geoffrey G
GG
Elgersma
Ype
Y
Zhu
Yuan
Y
Gutmann
David H
DH
Parada
Luis F
LF
Mody
Istvan
I
Silva
Alcino J
AJ
D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D016514:Genes, Neurofibromatosis 1; D006624:Hippocampus / Q000378:metabolism; D007858:Learning; D007859:Learning Disabilities / Q000503:physiopathology; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D009456:Neurofibromatosis 1 / Q000503:physiopathology; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D016704:Synapsins / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D025542:Neurofibromin 1; D016704:Synapsins; D005680:gamma-Aminobutyric Acid; D048049:Extracellular Signal-Regulated MAP Kinases