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Restored plasticity in a mouse model of neurofibromatosis type 1 via inhibition of hyperactive ERK and CREB

Lookup NU author(s): Professor Clare GuildingORCiD


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Patients with neurofibromatosis type 1 (NF1), resulting from neurofibromin gene mutations, frequently suffer from deficits in learning and spatial memory. Mice heterozygous for functional deletion of the NF1 gene (NF1(+/-) mice) also exhibit compromised spatial learning, and deficits in early-stage hippocampal long-term potentiation (LTP). Neurofibromin is a multifunctional protein which acts in part as an inhibitory constraint on Ras signalling, and the deficits in early-stage LTP and spatial learning have been linked to Ras hyperactivation. However, the downstream targets of Ras hyperactivation that lead to cognitive disruption are unknown. The levels of activity of signalling molecules potentially downstream of Ras were therefore studied in NF1(+/-) mice. Elevated phospho-ERK (pERK) levels were observed in the hippocampi from NF1(+/-) mice, while phospho-Akt/PKB (pAkt) and phospho-eIF4E (peIF4E) levels were unchanged relative to wild-type mice. Hippocampal levels of phospho-CREB (pCREB) were also increased, suggesting potential changes in late-phase LTP in NF1(+/-) mice. Indeed, LTP was found to be impaired for at least 4 h following induction in NF1(+/-) mice, linking neurofibromin function with the long-term maintenance of LTP. Remarkably, U0126, an inhibitor of ERK activation, at doses which reduced the hyperactive pERK levels in NF1(+/-) mice to the levels observed in control mice, caused a reduction in the deficits in early-phase LTP and completely rescued the long-term LTP deficits. In contrast to the abundant evidence that reductions in ERK activity lead to impaired plasticity, these data indicate that ERK hyperactivation in a partial model of type 1 neurofibromatosis leads to deficits in long-lasting hippocampal plasticity.

Publication metadata

Author(s): Guilding C, McNair K, Stone TW, Morris BJ

Publication type: Article

Publication status: Published

Journal: European Journal of Neuroscience

Year: 2007

Volume: 25

Issue: 1

Pages: 99-105

Print publication date: 01/01/2007

Online publication date: 12/01/2007

Acceptance date: 17/10/2006

Date deposited: 25/09/2015

ISSN (print): 0953-816X

ISSN (electronic): 1460-9568

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.1111/j.1460-9568.2006.05238.x

PubMed id: 17241271


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