Identifying mistranslating mRNAs in Fmr1-/y and Syngap+/- models of ASD/ID

Autism spectrum disorders and intellectual disability (ASD/ID) affect 1% of the population, yet there are no treatments that target the root cause of these disorders. In fragile X syndrome (FX) and SYNGAP1 haploinsufficiency syndrome, two common single-gene causes of ASD and ID, an imbalance in protein production (protein synthesis) is believed to be an underlying cause of many neurological symptoms. In this proposal, we will use a technologically advanced method to identify the proteins that are incorrectly produced in the neurons of the mouse models of FX and SYNGAP1 haploinsufficiency. This will lead to new information that may identify new treatment targets and guide new therapeutic strategies.

Exaggerated mRNA translation has been implicated in the neuropathology of two syndromic neurodevelopmental disorders linked to autism and intellectual disability (ASD/ID): fragile X syndrome (FX) and SYNGAP1 happloinsufficiency. This study will utilize Translating Ribosome Affinity Purification (TRAP) and RNA-seq to identify mistranslating mRNAs in key neuron populations in the Fmr1-/y and Syngap+/- mouse models of these disorders.

In Specific Aim 1, we will interrogate three neuron populations that are altered in both mutant models and may contribute to behavioural phenotypes: hippocampal CA1 pyramidal neurons, layer 5 medial prefrontal cortical (mPFC) neurons, and basolateral amygdala (BLA) neurons. In Specific Aim 2, we will examine the mRNAs translated in these neurons during fear learning in both mutant and WT. The comparison of differentially translating mRNAs in three key neuron populations during behaviour will allow for a powerful examination of the impact of altered protein synthesis in Fmr1-/y and Syngap+/- models.

Fragile X syndrome (FX) and SYNGAP1 haploinsufficiency are two of the most prevalent heritable causes of intellectual disability (ID) and of autism spectrum disorder (ASD). In recent years, much has been learned about the genetics of these and other neurodevelopmental disorders, yet there remains a profound lack of treatments that target the underlying pathophysiology. This proposal addresses the urgent need for better pharmacological strategies for treating FX, SYNGAP1 haploinsufficiency, and other genetic causes of ASD/ID by probing the molecular mechanisms that can serve as novel therapeutic targets.

The beneficiaries of the proposed research are many. Identification of new treatment strategies will relieve the burden on affected individuals and their families. Our results will be of significant value to clinical practitioners who design clinical trials, and who treat patients. The pharmaceutical industry will benefit from our findings by considering new therapies based on our results, and potentially designing new drugs.

It is estimated that the prevalence of ASD/ID in the UK is approximately 1%, and this results in significant costs necessary to care for affected individuals. The development of new treatments will thus relieve the government of a significant financial burden. Additionally, the University will benefit from this research if it results in new patents that generate revenue. The high-impact papers based on this research will also raise the academic and scientific profile of the University and UK research. Our research will also benefit charities devoted to the treatment of FX and ASD/ID by validating the value of the scientific research they support. Finally, the postdoctoral researcher and any Ph.D. or Masters students working on this project will benefit from training in multiple neuroscience techniques, and the exposure to cutting-edge research performed in the Edinburgh Neuroscience community.