During the 2012 funding period, we addressed the following: We measured rCPS in 15 male subjects (18-24 y) with the full fragile X mutation and 12 age-matched healthy volunteers. Because of their impairments it was necessary to study FXS subjects under deep sedation. We used propofol as the sedating agent. Each healthy volunteer was studied twice, once awake and once under propofol-sedation, and we found no differences in rCPS in whole brain or in any of the 10 regions examined. Contrary to our hypothesis, FXS subjects under propofol-sedation had statistically significantly reduced rCPS in whole brain, cerebellum, frontal and parietal cortex compared with sedated controls. We considered the possibility that propofol could have a disparate effect on rCPS in FXS subjects thereby masking a baseline elevation in rCPS, and we examined this possibility in the Fmr1 KO mouse model. Our study in adult Fmr1 KO mice showed that propofol results in widespread and significantly decreased rCPS throughout the brain whereas effects in WT mice were very circumscribed and smaller in magnitude. Our observation that treatment with a drug that alters neuronal and possibly synaptic activity also alters rCPS in Fmr1 KO mice has implications for the development of therapeutic strategies for FXS. A manuscript reporting these results is under review. We studied WT and Fmr1 KO mice untreated or treated with lithium-containing chow commenced at weaning and maintained throughout the experiment. Between 8 and 12 weeks of age, mice were subjected to the following behavioral tests: open field, social interaction, elevated plus maze, elevated zero maze and passive avoidance. At 13 weeks, brains were prepared for Golgi staining and analysis of dendritic spine morphology in medial prefrontal cortex. In separate groups of mice treated identically we measured rCPS at 12 weeks of age. We found that compared with untreated WT, untreated Fmr1 KO mice were hyperactive and had reduced anxiety, impaired social interactions, and deficits on the passive avoidance test. Dendritic spines in medial prefrontal cortex were longer and increased in number in Fmr1 KO mice. Lithium treatment ameliorated the hyperactivity and reversed impaired social interaction and learning deficits. Lithium treatment also normalized general anxiety levels and dendritic spine morphology. Moreover, chronic treatment with lithium reversed the increased rCPS found in Fmr1 KO mice and had little, if any, effect on rCPS in WT mice. Increased rCPS in the untreated Fmr1 KO mice compared with WT were found primarily in the limbic system and hypothalamus, whereas the effects of lithium occurred throughout the brain. We extended our studies to examine in hippocampus the effects of lithium treatment on some of the signaling pathways that influence translation. Our results indicate that neither effects on the PI3K/Akt nor the ERK 1/2 pathway can fully account for the effects on rCPS under the basal conditions of our study. Results of these studies were published in International Journal of Neuropsychopharmacology (Liu et al., 2011) and Neurobiology of Disease (Liu et al., 2012).

Project Start
Project End
Budget Start
Budget End
Support Year
33
Fiscal Year
2012
Total Cost
$1,117,731
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
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Zip Code
Saré, R Michelle; Levine, Merlin; Smith, Carolyn Beebe (2016) Behavioral Phenotype of Fmr1 Knock-Out Mice during Active Phase in an Altered Light/Dark Cycle. eNeuro 3:
Qin, Mei; Huang, Tianjian; Kader, Michael et al. (2015) R-Baclofen Reverses a Social Behavior Deficit and Elevated Protein Synthesis in a Mouse Model of Fragile X Syndrome. Int J Neuropsychopharmacol 18:
Qin, Mei; Zeidler, Zachary; Moulton, Kristen et al. (2015) Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome. Behav Brain Res 291:164-71
Qin, Mei; Huang, Tianjian; Liu, Zhonghua et al. (2014) Cerebral protein synthesis in a knockin mouse model of the fragile X premutation. ASN Neuro 6:
Qin, Mei; Schmidt, Kathleen C; Zametkin, Alan J et al. (2013) Altered cerebral protein synthesis in fragile X syndrome: studies in human subjects and knockout mice. J Cereb Blood Flow Metab 33:499-507
Lokanga, Rachel Adihe; Entezam, Ali; Kumari, Daman et al. (2013) Somatic expansion in mouse and human carriers of fragile X premutation alleles. Hum Mutat 34:157-66
Nadel, Jeffrey; Huang, Tianjian; Xia, Zengyan et al. (2013) Voluntary exercise regionally augments rates of cerebral protein synthesis. Brain Res 1537:125-31
Liu, Zhong-Hua; Huang, Tianjian; Smith, Carolyn Beebe (2012) Lithium reverses increased rates of cerebral protein synthesis in a mouse model of fragile X syndrome. Neurobiol Dis 45:1145-52
Ravasi, Laura; Shimoji, Kazuaki; Soto-Montenegro, Marisa L et al. (2011) Use of [18F]fluorodeoxyglucose and the ATLAS small animal PET scanner to examine cerebral functional activation by whisker stimulation in unanesthetized rats. Nucl Med Commun 32:336-42
Qin, M; Xia, Z; Huang, T et al. (2011) Effects of chronic immobilization stress on anxiety-like behavior and basolateral amygdala morphology in Fmr1 knockout mice. Neuroscience 194:282-90

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