|The Neurobiology of Fragile X Syndrome: A Unifying Neuro-Endocrine Hypothesis
by Abdeslem El Idrissi, 4/1/2007
Our preliminary data shows that the expression of somatostatin is significantly
decreased in the brain of fragile x as compared to controls. Furthermore, the reduced
expression of this neuropeptide is consistent with both central and peripheral features of
the fragile X syndrome. We show that treatment with taurine in drinking water caused a
significant increase in somatostatin expression both in controls and fragile X KO mice.
The increased expression of somatostatin in the fragile X KO mouse brain reversed
some of the features associated with the KO mutation in these mice.
This raises the possibility that either somatostatin or taurine could be employed as potential therapies
for fragile X; while somatostatin must be infused intravenously, taurine is available as an OTC nutritional
supplement (in fact, it's the main ingredient in Red Bull). This project will confirm the preliminary
results, and extend them with further trials of agents which enhance somatostatin function.
by Abdeslem El Idrissi, 3/2006
Fragile X syndrome includes hyperarousal, hypersensitivity to sensory stimuli, and an increased prevalence
of seizures. The mouse model for this disorder has increased seizure susceptibility, a feature that is
intrinsically dependent on hyperexcitability of neurons. Alterations in the GABAergic system have been
associated with the onset of hyperexcitability. Our investigations of the molecular basis of increased
seizure susceptibility in the fragile X mouse indicated a reduction in GABAA receptor expression. Since
these receptors play a major role in inhibition, their reduction helps explain the increased seizure
susceptibility of this mouse model for fragile X and suggest that the GABAergic system is affected in
the fragile X syndrome. We also found other biochemical changes occurring in the brain of fragile X mouse
that seem to be compensatory mechanisms to increased excitability. These include increased expression of
the enzyme responsible for the synthesis of GABA, the neurotransmitter agonist for GABAA receptors.
In our previous studies, we have shown that mice chronically supplemented with taurine in their drinking
water showed biochemical changes in the GABAergic system that are similar to those observed in fragile X
mice. Taurine is an amino acid that acts as an agonist for GABAA receptors (making them more sensitive).
Supplementation of taurine in drinking water for four weeks induces a variety of biochemical, architectural
and electrophysiological changes in the inhibitory GABAergic system. These changes include increases in the
levels of the neurotransmitters GABA, increased expression of glutamic acid decarboxylase, decreased
hippocampal expression of the subunits of the GABAA receptor. Taurine-fed mice, like fragile X mice
have reduced threshold for kainic acid-induced seizures. However, unlike fragile X mice, taurine-fed
mice showed a significant improvement in age-dependent decline in spatial learning.
We have used
a unique comparative approach, between the fragile X and taurine-fed mice, and examined divergent events
downstream of the biochemical changes in the GABAergic system in these two mouse models. Furthermore, we
looked for neuronal markers that are differentially expressed in fragile X and taurine-fed mice that might
explain the phenotypic discrepancies between these two mouse models (mainly learning deficit). In addition,
this neuronal marker should show an involvement as well as a correlation with most, if not all, fragile
Our preliminary data shows that the expression of somatostatin is significantly decreased in the brain of
fragile X as compared to the taurine-fed mice. Furthermore, the reduced expression of this neuropeptide is
consistent with both central and peripheral features of the fragile X syndrome. Understanding the regional
distribution of this neuropeptide and its receptors would allow us to target specific brain regions with
the hope of normalizing their function.