|Efficient screening for pharmaceutical amelioration of FXS behavioral deficits in Drosophila
by Efthimios Skoulakis, 4/1/2010
Patients with Fragile X syndrome (FXS) present a range of developmental and behavioural deficits with mild to severe mental retardation, attention deficit disorder, autistic behaviours and problems related to anxiety such as hyperactivity among others. FXS results from loss of FMR1 gene expression often by CGG triplet expansion in the 5’ untranslated region of the gene. Recently even in carriers of CGG expansion permutation in the fmr1 gene were found to suffer age dependent ataxia, short term memory difficulties, anxiety and irritability (FXTAS). Based on the multiple molecules that interact with the FMR Protein (FMRP) in the various neurons of the nervous system, we suggested that the broad range of behavioral deficits associated with FXS reflect impairment of distinct processes in neuronal circuits mediating these particular behaviours and may then requires specific pharmaceutical treatment to ameliorate them.
In the laboratory we work with a Drosophila model of FXS where affected fruitflies display learning and memory difficulties, attention deficits and hyperactivity. We have been using this model to test pharmaceuticals like the mGlu receptor inhibitors MPEP and Fenobam for amelioration of these behavioural difficulties. In accord with our hypothesis, we find that particular pharmaceuticals are best at ameliorating particular symptoms and so good towards control of others. This suggested to us that pharmaceutical “cocktails” are the most likely approach at controlling all symptoms, or the majority exhibited by a particular patient.
Therefore, with FRAXA support, we developed a fast and efficient method to screen through pharmaceuticals that control hyperactivity, a symptom not ameliorated by mGlu receptor inhibitors. Affected flies fed pharmaceuticals are automatically monitored for their locomotor activity which in untreated individuals is at least twice as much as that of controls.
Our continuing screen has identified a couple of previously unexpected compounds to affect the hyperactivity of the FXS flies and in a next step we will be testing mixtures of these with mGlu receptor inhibitors whether they also ameliorate learning, memory and attention difficulties. The screen will continue until all major classes of pharmaceuticals that target molecules known to serve learning, memory, attention and anxiety/hyperactivity have been tested. We also hope to test their efficacy on a model of FXTAS in the near future.