Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.
Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans. Mice carrying a heterozygous null mutation of the Nfl gene (Nfl(+/-) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity, adenylyl cyclase modulation and microtubule binding, it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1(+/-) mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1.
Costa
Rui M
RM
Departments of Neurobiology, Psychiatry and Psychology, BRI, University of California at Los Angeles, Los Angeles, California 90095-1761, USA.
Federov
Nikolai B
NB
Kogan
Jeff H
JH
Murphy
Geoffrey G
GG
Stern
Joel
J
Ohno
Masuo
M
Kucherlapati
Raju
R
Jacks
Tyler
T
Silva
Alcino J
AJ
D000818:Animals; D004195:Disease Models, Animal; D011905:Genes, ras; D006624:Hippocampus / Q000502:physiology; D066298:In Vitro Techniques; D007859:Learning Disabilities / Q000209:etiology* / Q000503:physiopathology; D017774:Long-Term Potentiation; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009433:Neural Inhibition; D009456:Neurofibromatosis 1 / Q000150:complications* / Q000503:physiopathology; D025542:Neurofibromin 1 / Q000172:deficiency / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D025542:Neurofibromin 1; D005680:gamma-Aminobutyric Acid; D018631:ras Proteins