The genetic basis of intellectual disability (ID) is extremely heterogeneous and relatively little is known about the role of autosomal recessive traits. However, in recent years, advances in technology have put development of induced pluripotent stem cells (iPSCs), and further differentiation into neuronal cells, at the forefront of neurological research. The use of iPSC-derived cells allows investigation of the effects of genetic mutations on neuronal cell function. Accordingly, we propose a research internship in Dr. Fred Gage Lab (Salk Institute, La Jolla, CA), who has a strong publication track record on using neurons derived from induced pluripotent stem cells to study various aspects of neuronal development in neurological diseases such Autism, Schizophrenia and Bipolar Disorder. Our plan is to develop and characterize hippocampal neuronal cell lines derived from patients with severe ID and disruptive behavior associated with a mutation in the inositol monophosphatase 1 (IMPA1) gene. The IMPA1 gene product is responsible for the final step of biotransformation of inositol triphosphate and diacylglycerol, two second messengers. Additionally, IMPA1 is the main target of lithium, a drug that is at the forefront of treatment for bipolar disorder. We described a novel 5-bp duplication leading to a frameshift and a premature stop codon in homozygous in nine individuals with ID and disruptive behavior that co-segregated in 70 genotyped family members from Northeastern Brazil. Based on these important preliminary findings, it is now essential to expand the studies to patient-derived neuronal cell lines in order to clearly elucidate the mechanisms by which impairment of IMPA1 can alter important signaling pathways that may lead to development of ID. We will investigate the effect of the mutation on disruption of signaling pathway networks, morphological and electrophysiological properties. The proposed work will set the stage for future studies including cell response to inositol, epigenetic changes, astrocyte-neuron interactions and correlation with in vivo measures of brain activity and cognitive capacity to better understand the pathway from genetic variants to behavior.
News published in Agência FAPESP Newsletter about the scholarship: