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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS091220-01
Application #
8861510
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Mamounas, Laura
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
Overall Medical
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Ka, Minhan; Kim, Woo-Yang (2017) ANKRD11 associated with intellectual disability and autism regulates dendrite differentiation via the BDNF/TrkB signaling pathway. Neurobiol Dis 111:138-152
Ka, Minhan; Smith, Amanda L; Kim, Woo-Yang (2017) MTOR controls genesis and autophagy of GABAergic interneurons during brain development. Autophagy 13:1348-1363
Ka, Minhan; Moffat, Jeffrey J; Kim, Woo-Yang (2017) MACF1 Controls Migration and Positioning of Cortical GABAergic Interneurons in Mice. Cereb Cortex 27:5525-5538
Jung, Eui-Man; Moffat, Jeffrey Jay; Liu, Jinxu et al. (2017) Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior. Nat Neurosci 20:1694-1707
Moffat, Jeffrey J; Ka, Minhan; Jung, Eui-Man et al. (2017) The role of MACF1 in nervous system development and maintenance. Semin Cell Dev Biol 69:9-17
Ka, Minhan; Kook, Yeon-Hee; Liao, Ke et al. (2016) Transactivation of TrkB by Sigma-1 receptor mediates cocaine-induced changes in dendritic spine density and morphology in hippocampal and cortical neurons. Cell Death Dis 7:e2414
Ka, Minhan; Chopra, Divyan A; Dravid, Shashank M et al. (2016) Essential Roles for ARID1B in Dendritic Arborization and Spine Morphology of Developing Pyramidal Neurons. J Neurosci 36:2723-42
Ka, Minhan; Kim, Woo-Yang (2016) Microtubule-Actin Crosslinking Factor 1 Is Required for Dendritic Arborization and Axon Outgrowth in the Developing Brain. Mol Neurobiol 53:6018-6032
Moffat, Jeffrey J; Ka, Minhan; Jung, Eui-Man et al. (2015) Genes and brain malformations associated with abnormal neuron positioning. Mol Brain 8:72