Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome

Abstract

Fragile X syndrome, the most frequent form of hereditary mental retardation, is due to a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome. Like fragile X patients, FMR1-knockout (FMR1-KO) mice lack the normal fragile X mental retardation protein (FMRP) and show both cognitive alterations and an immature neuronal morphology. We reared FMR1-KO mice in a C57BL͞6 background in enriched environmental conditions to examine the possibility that experience-dependent stimulation alleviates their behavioral and neuronal abnormalities. FMR1-KO mice kept in standard cages were hyperactive, displayed an altered pattern of open field exploration, and did not show habituation. Quantitative morphological analyses revealed a reduction in basal dendrite length and branching together with more immatureappearing spines along apical dendrites of layer five pyramidal neurons in the visual cortex. Enrichment largely rescued these behavioral and neuronal abnormalities while increasing ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit 1 (GluR1) levels in both genotypes. Enrichment did not, however, affect FMRP levels in the WT mice. These data suggest that FMRP-independent pathways activating glutamatergic signaling are preserved in FMR1-KO mice and that they can be elicited by environmental stimulation.fragile X mental retardation protein ͉ mental retardation ͉ FMR1 gene ͉ AMPA receptor ͉ dendritic spines S everal genes associated with mental retardation have been mapped on the X chromosome and, among them is the fragile X mental retardation 1 (FMR1) gene. The fragile X mental retardation protein (FMRP) absence or mutation is responsible for the fragile X syndrome (FXS), which is the most common form of inherited mental retardation. Most of the individuals affected carry a trinucleotide repeat that, after methylation, leads to transcriptional silencing of the FMR1 gene (1). Patients with the FXS do not express FMRP and exhibit phenotypic traits ranging from severe (IQ 20) to moderate (IQ 60) mental retardation, defective attention, autistic behavior, and physical features including an elongated face, large ears, joint laxity, and macroorchidism (2-5).FMR1 is highly conserved between human and mouse, with a nucleotide and amino acid identity of 95% and 97%, respectively (6). The expression pattern of mouse FMR1 is similar to its human counterpart in both tissue specificity and timing (7). Interestingly, FMR1-knockout (FMR1-KO) mice, the mouse model for the FXS, lack the normal FMRP and show macroorchidism, hyperactivity, and mild learning deficits (8, 9) reminiscent of the human syndrome.One common brain feature of fragile X patients and of the mouse model for the syndrome is the presence of long and thin immature dendritic spines indicative of defective pruning during development (10)(11)(12)(13)(14). At the molecular level, it has been shown that protein synthesis triggered by the type I metabotropic glutamate receptor (mGluR1) agonist dihydroxyphenylglycine is dramati...

Advances in behavioral genetics: mouse models of autism

“…Other variables for consideration include differences in laboratory procedures, testing and housing conditions, breeding milieu, and diversity of environmental stimuli. For example, Restivo and colleagues 59 found that exposure to an enriched environment can not only reverse some behavioral deficits in the Fmr1-null mouse, but can also fully rescue aberrant dendritic morphology in the FXS model. On the other hand, alterations in function of the hypothalamic-pituitary-adrenal axis, as observed in Fmr1-null mice 334 (see also Ref.…”

Age-Dependent and Selective Impairment of Long-Term Potentiation in the Anterior Piriform Cortex of Mice Lacking the Fragile X Mental Retardation Protein

“…Because suppressing expression of GluR1 can inhibit expression of stable LTP (Vanderklish et al, 1992;Zamanillo et al, 1999), this provides one mechanism by which absence of FMRP could indirectly reduce LTP. It should be noted, however, that a recent study did not find decreased expression of GluR1 in visual cortex of Fmr1 KO mice (Restivo et al, 2005); whether GluR1 subunits are altered in piriform cortex remains to be determined.…”

Environmental enrichment as an effective treatment for autism: A randomized controlled trial.

“…Fragile X syndrome, which arises with a mutation of the FMR1 gene, also shares symptoms with autism. Sensorimotor enrichment similarly rescues Fmr1-knockout mice from cognitive deficiencies (Restivo et al, 2005).…”