Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice.
Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. Here we show that systemic treatment of MeCP2 mutant mice with an active peptide fragment of Insulin-like Growth Factor 1 (IGF-1) extends the life span of the mice, improves locomotor function, ameliorates breathing patterns, and reduces irregularity in heart rate. In addition, treatment with IGF-1 peptide increases brain weight of the mutant mice. Multiple measurements support the hypothesis that RTT results from a deficit in synaptic maturation in the brain: MeCP2 mutant mice have sparse dendritic spines and reduced PSD-95 in motor cortex pyramidal neurons, reduced synaptic amplitude in the same neurons, and protracted cortical plasticity in vivo. Treatment with IGF-1 peptide partially restores spine density and synaptic amplitude, increases PSD-95, and stabilizes cortical plasticity to wild-type levels. Our results thus strongly suggest IGF-1 as a candidate for pharmacological treatment of RTT and potentially of other CNS disorders caused by delayed synapse maturation.
Tropea
Daniela
D
Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Giacometti
Emanuela
E
Wilson
Nathan R
NR
Beard
Caroline
C
McCurry
Cortina
C
Fu
Dong Dong
DD
Flannery
Ruth
R
Jaenisch
Rudolf
R
Sur
Mriganka
M
D000200:Action Potentials; D000818:Animals; D001921:Brain; D004195:Disease Models, Animal; D006339:Heart Rate; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology* / Q000627:therapeutic use; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity; D009474:Neurons; D009929:Organ Size; D015518:Rett Syndrome / Q000188:drug therapy*; D015996:Survival Rate; D009435:Synaptic Transmission; D016896:Treatment Outcome
D051783:Methyl-CpG-Binding Protein 2; D007334:Insulin-Like Growth Factor I