Lithium reverses increased rates of cerebral protein synthesis in a mouse model of fragile X syndrome.
Individuals with fragile X syndrome (FXS), an inherited form of cognitive disability, have a wide range of symptoms including hyperactivity, autistic behavior, seizures and learning deficits. FXS is caused by silencing of FMR1 and the consequent absence of fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that associates with polyribosomes and negatively regulates translation. In a previous study of a mouse model of FXS (Fmr1 knockout (KO)) we demonstrated that in vivo rates of cerebral protein synthesis (rCPS) were elevated in selective brain regions suggesting that the absence of FMRP in FXS may result in dysregulation of cerebral protein synthesis. Lithium, a drug used clinically to treat bipolar disorder, has been used to improve mood dysregulation in individuals with FXS. We reported previously that in the Fmr1 KO mouse chronic dietary lithium treatment reversed or ameliorated both behavioral and morphological abnormalities. Herein we report that chronic dietary lithium treatment reversed the increased rCPS in Fmr1 KO mice with little effect on wild type mice. We also report our results of analyses of key signaling molecules involved in regulation of mRNA translation. Our analyses indicate that neither effects on the PI3K/Akt nor the MAPK/ERK 1/2 pathway fully account for the effects of lithium treatment on rCPS. Collectively our findings and those from other laboratories on the efficacy of lithium treatment in animal models support further studies in patients with FXS.
Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Zhong-Hua
ZH
Liu
Tianjian
T
Huang
Carolyn Beebe
CB
Smith
D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects*; D004032:Diet; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008094:Lithium / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D051860:Fragile X Messenger Ribonucleoprotein 1; D008094:Lithium; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C497684:Fmr1 protein, mouse; C546843:mTOR protein, mouse