The relationship between brain overgrowth and the behavioral and cognitive symptoms of ASD is poorly understood. For example, PTEN is a susceptibility gene for autism spectrum disorder (ASD) and macrocephaly that is broadly expressed in the brain throughout development and adulthood. It also encodes a key regulator of a pathway-PI3K-Akt-mTOR-that is strongly implicated in ASD pathogenesis and treatment, as well as basic control of cellular growth. At present, we lack a mechanistic understanding of how changes in the trajectory of brain growth caused by germline PTEN mutations relates to the behavioral and cognitive symptoms of ASD and the assembly of underlying neural circuitry. Our overall goal is to bridge this gap in our knowledge by making use of a mouse model of PI3K-Akt-mTOR pathway dysregulation and brain overgrowth. The novel hypothesis that we develop here is that one effect of Pten mutations is to desynchronize the normal pattern of growth in key cell types relevant for social behavior, thus diverting the downstream connectivity and synaptic function of circuitry underlying social behavior toward a pathological state. We speculate that dopaminergic neurons in the VTA are a candidate cell type for this effect. We propose to carry out this work by characterizing developing and adult Pten haploinsufficient mice for brain growth trajectory and social behavioral phenotypes, by examining whether genetic and pharmacological suppression of 5-HT2cR during development and in adulthood can reverse these phenotypes, and by investigating whether dopaminergic neurons may be a cell type relevant to these effects. The proposed research will contribute to our knowledge of the neurobiology of autism through uncovering a mechanism by which Pten influences brain growth and the development of social behavior via the regulation of 5-HT2cR in dopaminergic neurons. This contribution will be significant because it will be the first step in a line of research expected to lead to novel pharmacogenetic approaches that will allow for circuit-level corrections of social behavioral deficits specific to a given ASD risk factor at the level of cell type growth. Furthermore, this proposal is innovative because it grounds the study of autism, the PI3K-Akt-mTOR pathway and regulation of brain growth at the level of a specific G-protein coupled receptor (GPCR)-neural cell type interaction important for social behavior. As such strategies become available, there is the prospect that therapeutic approaches could be rationally selected for the symptoms of a given individual with ASD based on the unique set of risk factors they have been exposed to. Thus, we can expect that this research will lead to important advances in the treatment of ASD and other neuropsychiatric disorders that feature social behavioral deficits, altered brain growth and/or dysregulation of the PI3K-Akt-mTOR pathway. Furthermore, this line of investigation will provide broader insight into how social behavior develops at the level of specific cell types and circuits in the brain, and how the regulation of neuromodulatory GPCRs contributes to this process.
Autism spectrum disorder (ASD) is a disorder of the developing brain that has a profound impact at the individual and societal level and is characterized by heterogeneity in symptoms and risk factors. We are using a mouse model to investigate how Pten, an ASD risk gene well linked to macrocephaly and a key pathway dysregulated in ASD, impacts the development of brain circuits relevant for the symptoms of ASD. Understanding the biology of how PTEN influences the development of brain circuits will lead us to specific approaches to diagnose and treat a subset of individuals with ASD.
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