With a $74,000 grant from FRAXA Research Foundation, Dr. Abdeslem El Idrissi at CUNY explored the GABA receptor system in Fragile X mice and tested somatostatin and taurine as potential therapies for Fragile X; while somatostatin must be infused intravenously, taurine is available as a nutritional supplement. Taurine showed good results.
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 X-specific features. 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.
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.