Intellectual disability that limits normal cognitive functioning and skill learning affects 1-3% of the population of the United States. Associated neurological conditions include autism, Coffin-Siris Syndrome, Miller-Dieker syndrome, Down Syndrome, Fragile X syndrome, Fetal Alcohol Spectrum Disorder, and microcephaly. This disability appears during childhood and leads to impairments in learning and acquisition of critical daily skills. This is a life-long problem, affecting the cost of long-term education and employment. Although intellectual disability is a clinically important disorder, the etiology and pathogenesis are poorly understood. Accordingly, pharmacological or genetic intervention does not currently exist. Recently, AT-rich interactive domain containing protein 1B (ARID1B), a member of SWI/SNF chromatin remodeling complex, has been identified as a causative factor for a several syndromic and nonsyndromic conditions associated with intellectual disability and autism. However, the neural function of this gene during brain development is unknown. The goal of this proposal is to define the role of ARID1B in neuronal development and establish an animal model for intellectual disability. Our preliminary data revealed that ARID1B plays important roles in positioning and differentiation of radially-migrating excitatory pyramidal neurons in the mammalian developing brain. Based on our preliminary results, we hypothesize that loss of ARID1B functions disrupts normal neuronal migration and dendritic/synaptic development in the developing brain. Using a combination of mouse genetics and molecular/biochemical approaches, we will test this hypothesis by examining the following related aims:
Aim 1) Determine the requirement of ARID1B in cell-type- specific positioning and migration in the developing brain;
Aim 2) Define the role of ARID1B in dendritic morphogenesis and synaptic plasticity in the developing brain;
Aim 3) Characterize behavioral phenotypes of ARID1B knockout mice;
and Aim 4) Determine if reinforcing TrkB/PI3K signaling rescues neuronal defects caused by ARID1B gene deletion. This study is expected to provide novel insights into the pathogenic mechanisms of intellectual disability, and establish an appropriate animal model for this condition. Furthermore, the outcome of this study will serve as a basis for developing treatment strategies for intellectual disability.
Disruption in neuronal development underlies pathogenic mechanisms of intellectual disability and its associated neurological conditions including autism, Down syndrome, Fragile X syndrome, Fetal Alcohol Spectrum Disorder, and microcephaly. The goal of this proposed study is to define the roles of a causative gene in neuronal development and establish a novel animal model. Therefore, the successful completion of our study will provide important and novel insights into the molecular mechanisms underlying the pathogenesis of intellectual disability and, in turn, contribute to the development of potential preventative strategies.
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