May 25, 2007 — A new study of the
malfunctioning neuronal machinery of Fragile X syndrome reveals that it
can be restored by a stimulating environment. The study found that mice
genetically altered to have the same defect as humans with the disorder
benefited from an environment with constantly changing toys and access
to "play cages." Fragile X syndrome is the most common form of
inherited mental retardation, occurring in 1 in 3600 males and 1 in
4000 to 6000 females.
To understand the details of the neuronal pathology of Fragile X
syndrome, the researchers, led by Huibert Mansvelder, studied mice in
which the same gene that causes the disease in humans had been knocked
out. The scientists performed a detailed analysis of the
electrophysiological properties of neurons in the prefrontal cortex, a
region responsible for higher cognitive functions, including learning
and memory, that are affected in humans with the disorder.
The scientists’ analysis revealed that the neurons in the mice
showed reduction of a particular form of a process called "long-term
potentiation" that is central to the formation of new circuit pathways
in learning and memory. The researchers’ experiments showed that this
reduction was due to abnormalities in the pore-like channels that
regulate the flow of calcium into neurons.
Importantly, they found that increased stimulation of neurons in the
mice, which enhanced calcium signaling, could restore normal long-term
potentiation and neuronal plasticity.
There have been reports that Fragile X patients can still learn and
memorize information but need more repetition and stimulation. Also,
studies by other researchers had shown that exposing Fragile X knockout
mice to a stimulating environment ameliorated behavioral and neuronal
So, Mansvelder and colleagues tested whether exposure of the
knockout mice to an enriched environment caused higher stimulation that
would restore normal neuronal plasticity. They gave such mice a variety
of cage toys, and also gave them time in play cages that contained
running wheels, tunnels, different bedding material, and interesting
The researchers found that such an enriched environment did, indeed,
restore normal neuronal plasticity. The researchers concluded that
"increased sensory, cognitive, and motor stimulation by environmental
enrichment facilitates the development of synaptic plasticity in
cortical areas involved in higher cognitive function. The results of
this study demonstrate that in prefrontal cortex of Fragile X knockout
mice, excitatory synapses can show lasting increases in synaptic
strength, but this requires increased neuronal activity to occur."
The researchers include Rhiannon M. Meredith, Carl D. Holmgren,
Meredith Weidum, Nail Burnashev, and Huibert D. Mansvelder, VU
University Amsterdam in Amsterdam.
This work was supported by grants from the Dutch Medical Research
Council (ZonMW, 911-03-014 to H.D.M. and 912-04-022 to H.D.M. and N.B.)
and the Royal Netherlands Academy of Arts and Sciences (KNAW, to
H.D.M.). The Department of Experimental Neurophysiology was financially
supported by NeuroBsik .
Reference: Meredith et al.: "Increased Threshold for
Spike-Timing-Dependent Plasticity Is Caused by Unreliable Calcium
Signaling in Mice Lacking Fragile X Gene Fmr1." Publishing in Neuron
54, 627–638, May 24, 2007. DOI 10.1016/j.neuron.2007.04.028.
Source : Cell Press