As increasing numbers of genetic differences are identified as susceptibility factors for psychiatric illness through modern sequencing and other types of studies, a growing challenge will be to understand how these differences affect molecular pathways that alter brain development and function and that thereby lead to mental illness. It will likewise become important to understand how therapeutic interventions interact with these same molecular pathways to improve and optimally to reverse) psychiatric symptoms. This NARSAD study focuses on interactions between several molecular components implicated by human genetic and other evidence in the origins of major mental illnesses including autism and schizophrenia, and tests a model for functional interactions between these molecules as part of a proposed biochemical feedback circuit within brain cells neurons) of the forebrain. The major components of this proposed feedback circuit include a microRNA that has been shown to be differentially expressed in neurons of the prefrontal cortex and in schizophrenic patients, a putative gene target of this microRNA with a potentially disruptive mutation in its regulatory region also associated with schizophrenia, and a major neurodevelopmental signaling pathway that affects synapse development and function. The investigator proposes that disruption of this molecular circuit within neurons of the prefrontal cortex in schizophrenia, autism, and possibly in other psychiatric conditions leads to changes in synapse development and function, and that this in turn leads to symptomatic behavioral disruption. The investigator and his laboratory staff have demonstrated in preliminary research that mice engineered to have targeted disruption in one of the molecules in this circuit, even on only one of two chromosomes heterozygotes), display decreased motivation that is responsive to the psychotherapeutic drug lithium, an established regulator of the neurodevelopmental pathway proposed as another circuit component. They have also shown that these animals have defects in the development of synapses in forebrain neurons. In this project they will use these animals and cell-based models to test whether elements of this proposed circuit do indeed from a molecular feedback loop in developing forebrain neurons, whether disruption of this feedback loop leads to neurodevelopmental and behavioral changes reflective of psychiatric symptomatology, and whether pharmacologic intervention that normalizes this circuit can reverse these changes at biochemical, cellular, and behavioral levels.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
