Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.

Catherine H Choi,R Suzanne Zukin,David A Liebelt,Allison M Terlizzi,Danielle Emerson,Paul Hinchey,Steven Sust,Thomas A Jongens,Steven J Siegel,Richard J Choi,Thomas V Mcdonald,Steven Langer,Maria Kollaros,Steven E Arnold,Joseph Hinchey,Neal J Ferrick,David Ferreiro,Robert E Featherstone,Natalia Louneva,Eric Koenigsberg,Daniel B Chambers,Michael J Gertner,Aatika Malik,Brian P Schoenfeld,Cory Rosenfelt,Sammy C Campbell ,Abhijeet Sharma ,François V Bolduc ,Aaron Bell ,Sean Mcbride

doi:10.3389/fnbeh.2016.00136

Abstract

Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model.

Highlights

Fragile X syndrome is the most common monogenic cause of both intellectual disability and autism spectrum disorders (Turner et al, 1996; Crawford et al, 2002; Hagerman, 2008)
We did not use methyl-6-(phenylethynyl) pyridine (MPEP) for mouse work in this study since the focus is on cAMP signaling with regard to Fragile X models (Figure 1A) and in mammals at low doses MPEP is selective for mGluR5 along with having a very short half-life making chronic treatment difficult
MGluR antagonists and phosphodiesterase type 4 (PDE-4) inhibitors given in adulthood was able to increase social interaction, which is normally suppressed in the fragile X flies

Summary

Introduction

Fragile X syndrome is the most common monogenic cause of both intellectual disability and autism spectrum disorders (Turner et al, 1996; Crawford et al, 2002; Hagerman, 2008). A Drosophila model for Fragile X syndrome, based on the loss of dfmr expression, recapitulates several phenotypes observed in Fragile X including impairments in social interaction and several phases of memory including immediate recall memory, short term memory and long term memory (Zhang et al, 2001; Dockendorff et al, 2002; Morales et al, 2002; McBride et al, 2005; Bolduc et al, 2008, 2010). Treatments that rescue learning/immediate recall memory (0–2 min memory) or short term memory (60 min memory) may not rescue long term memory

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Conclusion