Intellectual disabilities (IDs) and autism spectrum disorders (ASDs) are co-occurring disorders that are first diagnosed at about 1-2 years of age. They affect approximately 2-3% of the population, between 1-2 million people in the UK alone have an ID/ASD. However, therapeutic approaches for these disorders tend to focus on managing symptoms using special education or medications that target specific symptoms such as anxiety and seizure. There is an urgent need to develop more effective treatments to reverse and/or prevent these brain disorders.Two areas of research have provided a sea change in how we envision potential treatments for ID/ASD. First, despite the fact that hundreds of genes have been implicated in causing ID/ASD, recent evidence suggests many genetic cause may share changes in brain development and hence treatment developed for one, may be effective for another. Second, while it was previously thought that there treatment would only be effective during early development when symptoms first appear, recent evidence suggests that at least some forms of these disorders may be treatable throughout the lifespan. Two of the most common genetic forms of ID/ASD are Fragile X Syndrome (FXS) and SYNGAP haploinsufficiency. Both result from genetic alteration of a single gene and hence, are relatively straightforward to study in the laboratory. Previous work from our laboratories indicates that these two disorders may share a common pathology in the hippocampus, the region of the brain responsible for many forms of learning and memory. Using novel rat models of these disorders, we propose to extend these studies to see whether they we also see similar changes in the regions of the brain that control emotion and anxiety, namely the amygdala and prefrontal cortex. We will also test whether any alterations can be prevented from emerging during development and can be rescued in older animals, once ID/ASD related symptoms have emerged. We will test three exciting new drug interventions that are currently being developed for treatment of FXS. Each intervention will be tested for their ability to rescue changes in brain cells, in the connections between brain cells, as well as the behavioural consequences that result from these alterations in brain development.Technical SummaryIntellectual disabilities (IDs) and autism spectrum disorders (ASDs) are co-occurring neurodevelopmental disorders (NDDs). With a prevalence estimated at 2-3% of the population, between 1-2 million people in the UK alone have an ID/ASD. The urgent unmet need, therefore, is to develop more effective therapeutics to reverse and/or prevent the emergence of the core deficits associated with ID/ASD.Two areas of research have provided a sea change in how we envision potential treatments for NDDs. First, evidence suggests that genetically disparate NDDs converge on relatively few axes of pathophysiology that are susceptible to common therapeutic intervention. Second, at least some forms of these disorders may be treatable throughout the lifespan. The experiments outlined in this proposal take advantage of two recently developed rat models for FXS and SYNGAP haploinsufficiency, two of the most common genetic forms of ID/ASD. It builds on our recent publications and preliminary data to address these key research areas.The experiments outlined in this proposal will test our two hypotheses:1) FXS and SYNGAP haploinsufficiency converge on common pathophysiology in the hippocampus, prefrontal cortex and amygdala. 2) The cellular and behavioural phenotypes associated with loss of FMRP and SYNGAP can be reversed throughout the lifespan in an age, treatment, and circuit-specific manner.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
