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Section on Neuroadaptation
and Protein Metabolism

FXS KO Mouse

The KO mouse does not express FMRP and appears to be a good animal model for the human disorder. The KO mouse model permits an assessment of the effect of the fmr1 mutation on a constant genetic background.

KO Mouse

Characteristics of the KO mouse

  • macroorchidism
  • immature-appearing dendritic spines
  • subtle spatial learning abnormalities
  • auditory hypersensitivity
  • increased susceptibility to audiogenic seizures

Our work in the KO mouse further examines

KI lab mouse
  • behavior
  • cerebral energy metabolism
  • cerebral protein synthesis
  • morphology
  • efficacy of drug treatment

Behavioral Studies

  • hyperactivity [1]
  • lower generalized anxiety [1,2,3]
  • impaired social interaction [2]
  • deficit in learning/memory [1,2,3]

Cerebral Energy Metabolism

In an effort to understand what brain regions are involved in FXS, we measured in vivo regional cerebral metabolic rates for glucose (rCMRglc) in KO mice. We found rCMRglc was higher in the brain as a whole (26%) and in regions (19-46%) of the limbic system and primary sensory and posterior parietal cortical areas [1]. Regions most affected were consistent with behavioral deficiencies and regions in which FMRP expression is highest in WT.

fxsfig1

Digitized [14C]deoxyglucose autoradiograms (B,D,F,H) and corresponding Nissl-stained sections (A,C,E,G) from WT (A-D) and fmr1 KO (E-H) mice. [1].)

Similar studies in adult female mice show that females homozygous for the KO, i.e., without FMRP, had behavioral characteristics similar to male KO mice [3]. Despite these behavioral differences, rCMRglc were unaffected throughout the brain in the female mice. These results suggest that estrogen may afford some protection from the effects of the mutation.

Cerebral Protein Synthesis

fxsfig2

FMRP is an RNA-binding protein that has been shown to suppress translation of certain mRNAs in vitro. We applied the quantitative autoradiographic L-[1-14C]leucine method [4] to determine rates of cerebral protein synthesis (rCPS) in adult male WT and fmr1 KO mice in vivo [5]. Our results demonstrate a regionally selective elevation in rCPS in fmr1 KO mice and support the hypothesis that FMRP is a suppressor of translation in brain in vivo. Regions of the brain most affected in the KO were hippocampus, thalamus, and hypothalamus. Most areas of neocortex were unaffected.

Morphology

fxsfig4

Immature appearing dendritic spines are a pathological hallmark of FXS. In the KO mouse abnormal dendritic spines are found in the somatosensory cortex, but only in young animals. We are examining dendritic branching and spine morphology in adult animals in several regions of brain in which we have detected changes in rCPS.

Efficacy of Drug Treatment

We are examining the efficacy of several proposed drug treatments of FXS in the KO mouse model:

  • MPEP (2-methyl-6-phenylethynyl-pyridine hydrochloride) an mGluR5 (metabotropic glutamate receptor subtype 5) antagonist. It has been proposed that reducing activation of mGluR5 can modulate symptoms of FXS. In fmr1 KO mice acute administration of MPEP normalized rCPS in hippocampus (Smith et al, unpublished).
  • Lithium chloride. Chronic treatment of fmr1 KO mice with dietary lithium reverses behavioral deficits [2].

Acknowledgement

This work is supported, in part, by the Fragile X Research Foundation.

References

[1] Qin M, Kang J, Smith CB. Increased rates of cerebral glucose metabolism in a mouse model of fragile X mental retardation. Proc Natl Acad Sci USA 2002, 99:15758-15763.

[2] Liu Z-H, Chuang D-M, Smith CB Lithium ameliorates deficits in mouse model of fraile X syndrome. Soc Neurosci 2008, 550.12.

[3] Qin M, Kang J, Smith CB. A null mutation for Fmr1 in female mice: Effects on regional cerebral metabolic rate for glucose and relationship to behavior. Neurosci 2005,135: 999-1009.

[4] Smith CB, Deibler GE, Eng N, Schmidt K, Sokoloff L. Measurement of local cerebral protein synthesis in vivo: Influence of recycling of amino acids derived from protein degradation. Proc Natl Acad Sci USA 1988, 85:9341-9345.

[5] Qin M, Kang J, Burlin TV, Jiang C, Smith CB. Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the Fmr1 null mouse. J Neuroscience 2005, 25(20):5087-5095.