Previous studies of autism spectrum disorder (ASD) have shown abnormalities in brain development, synaptic plasticity, and social and learning behavior. Our previous study has identified the X-linked gene KIAA2022, and its protein product KIDLIA, as the etiological factor in a particular group of patients with intellectual disability and ASD phenotypes. I found that KIDLIA is neuron specific and localized exclusively in the nucleus, indicating a possible role for KIDLIA in neuronal gene regulation. Using rat hippocampal neurons, I found that shRNA-mediated knockdown of KIDLIA resulted in a marked impairment of neurite outgrowth via the disruption of the N-cadherin/δ-catenin/RhoA signaling pathway. Additionally, I showed that loss of KIDLIA expression decreases synapse formation and synaptic transmission. To investigate the role of KIDLIA in vivo, I generated and characterized KIDLIA knockout (KO) mice. KIDLIA KO mice demonstrated significant impairments in social interactions, increased repetitive behaviors and deficits in learning and memory, consistent with symptoms observed in human ASD patients and validate this mouse line as a valuable new model for ASD. The KIDLIA KO mice showed reduced synapse formation and abnormal expression of synaptic components such as the GluA1 subunit of AMPA receptors. To understand the potential role of KIDLIA in gene regulation, I used RNAseq to identify major candidates involved in synapse formation and function and discovered the synapse-enriched Ca2+-mediated protein, neurogranin, as the most down-regulated synaptic transcript. I showed that over-expression of neurogranin can rescue KIDLIA-dependent structural and functional synaptic deficits. This study provides valuable insight into the cellular and molecular mechanisms underlying KIDLIA-dependent autism and intellectual disability phenotypes. / 2018-11-08T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/27069 |
| Date | 08 November 2017 |
| Creators | Gilbert, James Patrick |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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