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Title: Poster session: The sterol synthesis inhibitor lovastatin rescues impaired hippocampal synaptic plasticity in a mouse model of Legius syndrome, a novel NF1-like-syndrome
Authors: Ahmed, Tariq
Denayer, E.
Sabanov, Victor
D'Hooge, Rudi
Legius, Eric
Balschun, Detlef #
Issue Date: Jul-2010
Host Document: FENS abstract vol:5
Conference: FENS Forum of European Neuroscience edition:7 location:Amsterdam date:3-7 July 2010
Article number: 166.1
Abstract: Spred proteins belong to a novel family of evolutionary conserved, negative regulators of the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. Germline mutations in SPRED1 were recently shown to cause a neurofibromatosis type 1 (NF1) -like syndrome (Legius syndrome) in children that included learning difficulties, the inference being that SPRED1 is involved in neural and behavioural plasticity. We investigated hippocampus-dependent synaptic plasticity in Spred1 knock-out mice, an animal model of this newly described human syndrome.
Spred1 knockout mice when examined for synaptic plasticity in the hippocampal CA1 region in vitro, displayed decremental long-term potentiation (LTP) after theta-burst stimulation (TBS). In contrast, LTP in WT littermates was robust and maintained for at least 4 h (Denayer et al., 2008). A similar result was reported for the NF1+/- mouse model. Furthermore, treatment of NF1+/- mice with: (1) picrotoxin, a GABAA antagonist rescued the phenotype and; (2) with a sterol synthesis inhibitor (statin) resulted in amelioration of synaptic plasticity (Costa et al 2002; Li et al 2005). When a similar strategy was applied for Spred1 KO mice, picrotoxin normalized their smaller input/output values which are most likely caused by a higher tonic inhibition, but did not abolish the impairment of LTP. However, chronic treatment of Spred1 KO mice with the sterol synthesis inhibitor lovastatin rescued the LTP-deficit. Thus, delineating this pathway in cognition and synaptic plasticity may open up new therapeutic approaches for this and other NF1-like human disorders.
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Laboratory for Biological Psychology
Department of Human Genetics - miscellaneous
# (joint) last author

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