Alterations of amino acids and monoamine metabolism in male Fmr1 knockout mice: a putative animal model of the human fragile X mental retardation syndrome.

Michael Gruss,Katharina Braun

doi:10.1155/np.2001.285

Michael Gruss, Katharina Braun

Open Access

https://doi.org/10.1155/np.2001.285

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Abstract

The Fragile X syndrome, a common form of mental retardation in humans, is caused by silencing the fragile X mental retardation (FMR1) geneleading to the absence of the encoded fragile X mental retardation protein 1 (FMRP). We describe morphological and behavioral abnormalities for both affected humans and Fmr1 knockout mice, a putative animal model for the human Fragile X syndrome. The aim of the present study was to identify possible neurochemical abnormalities in Fmr1 knockout mice, with particular focus on neurotransmission. Significant region-specific differences: of basal neurotransmitter and metabolite levels were found between wildtype and Fmr1 knockout animals, predominantly in juveniles (post-natal days 28 to 31). Adults (postnatal days 209 to 221) showed only few abnormalities as compared with the wildtype. In juvenile knockout mice, aspartate and taurine were especially increased in cortical regions, striatum, hippocampus, cerebellum, and brainstem. In addition, juveniles showed an altered balance between excitatory and inhibitory amino acids in the caudal cortex, hippocampus, and brainstem. We detected very few differences in monoamine turnover in both age stages. The results presented here provide the first evidence that lack of FMRP expression in FMRP knockout mice is accompanied by age-dependent, region-specific alterations in neurotransmission.

Highlights

The Fragile X syndrome, associated with a chromosomal abnormality, is one of the most common forms of inherited mental retardation in humans (Oostra, 1996; Jin & Warren, 2000)
The Fragile X syndrome, a common form of mental retardation in humans, is caused by silencing the fragile X mental retardation (FMR1) gene leading to the absence of the encoded fragile X mental retardation protein 1 (FMRP)
Hippocampus, and brainstem of the juvenile Fmrl knockout mice, the balance between excitatory and inhibitory amino acids was shifted toward increased inhibition (Table 1), whereas in adults no difference was found

Summary

Introduction

The Fragile X syndrome, associated with a chromosomal abnormality, is one of the most common forms of inherited mental retardation in humans (Oostra, 1996; Jin & Warren, 2000). The Fragile X syndrome is based on a large expansion of a CGG repeat sequence (more than 200 to 230 copies in the full mutation) in the 5"- untranslated region of the fragile X mental retardation (FMRI) gene (Fu et al, 1991; Oberle et al, 1991 Verkerk et al, 1991) Caused by this repeat expansion, a hyper-methylation takes place in a CpG island, including the promotor region, resulting in an inactivation of the fragile X mental retardation protein gene (FMRI gene), loss of expression of FMRI mRNA transcripts (Pieretti et al, 1991), M. Immature spine morphology and reduced synaptic size have been observed in autopsy material from patients suffering from Fragile X syndrome (Rudelli et al, 1985; Hinton et al, 1991 Irwin et al, 2000; 2001)

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