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Neurofibromin regulation of ERK signaling modulates GABA release and learning.

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.

SUBMITTER: Cui Y

PROVIDER: S-EPMC2673196 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Neurofibromin regulation of ERK signaling modulates GABA release and learning.

Cui Yijun Y 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

Cell 20081001 3

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, in ...[more]

PMID: 18984165

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Project description:The severe defects in growth plate development caused by chondrocyte extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) gain or loss-of-function suggest that tight spatial and temporal regulation of mitogen-activated protein kinase signaling is necessary to achieve harmonious growth plate elongation and structure. We provide here evidence that neurofibromin, via its Ras guanosine triphosphatase -activating activity, controls ERK1/2-dependent fibroblast growth factor receptor (FGFR) signaling in chondrocytes. We show first that neurofibromin is expressed in FGFR-positive prehypertrophic and hypertrophic chondrocytes during growth plate endochondral ossification. Using mice lacking neurofibromin 1 (Nf1) in type II collagen-expressing cells, (Nf1col2(-/-) mutant mice), we then show that lack of neurofibromin in post-mitotic chondrocytes triggers a number of phenotypes reminiscent of the ones observed in mice characterized by FGFR gain-of-function mutations. Those include dwarfism, constitutive ERK1/2 activation, strongly reduced Ihh expression and decreased chondrocyte proliferation and maturation, increased chondrocytic expression of Rankl, matrix metalloproteinase 9 (Mmp9) and Mmp13 and enhanced growth plate osteoclastogenesis, as well as increased sensitivity to caspase-9 mediated apoptosis. Using wildtype (WT) and Nf1(-/-) chondrocyte cultures in vitro, we show that FGF2 pulse-stimulation triggers rapid ERK1/2 phosphorylation in both genotypes, but that return to the basal level is delayed in Nf1(-/-) chondrocytes. Importantly, in vivo ERK1/2 inhibition by daily injection of a recombinant form of C-type natriuretic peptide to post-natal pups for 18 days was able to correct the short stature of Nf1col2(-/-) mice. Together, these results underscore the requirement of neurofibromin and ERK1/2 for normal endochondral bone formation and support the notion that neurofibromin, by restraining RAS-ERK1/2 signaling, is a negative regulator of FGFR signaling in differentiating chondrocytes.

Project description:BackgroundThe skin is largely comprised of keratinocytes within the interfollicular epidermis. Over approximately two weeks these cells differentiate and traverse the thickness of the skin. The stage of differentiation is therefore reflected in the positions of cells within the tissue, providing a convenient axis along which to study the signaling events that occur in situ during keratinocyte terminal differentiation, over this extended two-week timescale. The canonical ERK-MAPK signaling cascade (Raf-1, MEK-1/2 and ERK-1/2) has been implicated in controlling diverse cellular behaviors, including proliferation and differentiation. While the molecular interactions involved in signal transduction through this cascade have been well characterized in cell culture experiments, our understanding of how this sequence of events unfolds to determine cell fate within a homeostatic tissue environment has not been fully characterized.MethodsWe measured the abundance of total and phosphorylated ERK-MAPK signaling proteins within interfollicular keratinocytes in transverse cross-sections of human epidermis using immunofluorescence microscopy. To investigate these data we developed a mathematical model of the signaling cascade using a normalized-Hill differential equation formalism.ResultsThese data show coordinated variation in the abundance of phosphorylated ERK-MAPK components across the epidermis. Statistical analysis of these data shows that associations between phosphorylated ERK-MAPK components which correspond to canonical molecular interactions are dependent upon spatial position within the epidermis. The model demonstrates that the spatial profile of activation for ERK-MAPK signaling components across the epidermis may be maintained in a cell-autonomous fashion by an underlying spatial gradient in calcium signaling.ConclusionsOur data demonstrate an extended phospho-protein profile of ERK-MAPK signaling cascade components across the epidermis in situ, and statistical associations in these data indicate canonical ERK-MAPK interactions underlie this spatial profile of ERK-MAPK activation. Using mathematical modelling we have demonstrated that spatially varying calcium signaling components across the epidermis may be sufficient to maintain the spatial profile of ERK-MAPK signaling cascade components in a cell-autonomous manner. These findings may have significant implications for the wide range of cancer drugs which therapeutically target ERK-MAPK signaling components.

Dataset Information

Neurofibromin regulation of ERK signaling modulates GABA release and learning.

Publications

Neurofibromin regulation of ERK signaling modulates GABA release and learning.

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