Age-dependent cognitive impairment in a Drosophila Fragile X model and its pharmacological rescue

Abstract

Fragile X syndrome afflicts 1 in 2,500 individuals and is the leading heritable cause of mental retardation worldwide. The overriding clinical manifestation of this disease is mild to severe cognitive impairment. Age-dependent cognitive decline has been identified in Fragile X patients, although it has not been fully characterized nor examined in animal models. A Drosophila model of this disease has been shown to display phenotypes bearing similarity to Fragile X symptoms. Most notably, we previously identified naive courtship and memory deficits in young adults with this model that appear to be due to enhanced metabotropic glutamate receptor (mGluR) signaling. Herein we have examined age-related cognitive decline in the Drosophila Fragile X model and found an age-dependent loss of learning during training. We demonstrate that treatment with mGluR antagonists or lithium can prevent this age-dependent cognitive impairment. We also show that treatment with mGluR antagonists or lithium during development alone displays differential efficacy in its ability to rescue naive courtship, learning during training and memory in aged flies. Furthermore, we show that continuous treatment during aging effectively rescues all of these phenotypes. These results indicate that the Drosophila model recapitulates the age-dependent cognitive decline observed in humans. This places Fragile X in a category with several other diseases that result in age-dependent cognitive decline. This demonstrates a role for the Drosophila Fragile X Mental Retardation Protein (dFMR1) in neuronal physiology with regard to cognition during the aging process. Our results indicate that misregulation of mGluR activity may be causative of this age onset decline and strengthens the possibility that mGluR antagonists and lithium may be potential pharmacologic compounds for counteracting several Fragile X symptoms.

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

“…Lithium treatment, which modulates signaling in a manner similar to mGluR antagonists, also increased naive courtship and restored short-term memory in FXS flies (McBride et al, 2005). A later study further found that treatment with mGluR antagonists or lithium effectively prevented age-related cognitive impairments in this Drosophila model of FXS (Choi et al, 2010).…”

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

“…The following strategies were confirmed in studies using Drosophila models of fragile X syndrome (FXS): metabotropic glutamate receptor (mGluR) [167], gamma-aminobutyric acid (GABA) [168] (but see [169]), lithium [167], minocycline [170], phosphodiesterase-4 (PDE-4) [ A recent study suggested that simultaneous stimulation of D1R and serotonin (5HT) receptors rescued impaired synaptic AMPA receptor insertion and plasticity, and improved fear conditioning and Y maze learning deficits [115]. § Simultaneous inhibition of mGlu5 and CB1R was additive in this study.…”

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

“…Therefore, social interactions such as naïve courtship were studied in aged dFmr1 mutant flies, but no further differences were reported in comparison to young flies (Choi et al 2010). Additional studies using dFmr1 transgenic flies expressing only proteins with mutations in the KH domains (I244N or I307N) revealed reduced naïve courtship activity, suggesting that this effect is likely due to the lack of dFMRP's ability to bind a specific subset of mRNAs (Banerjee et al 2007).…”