Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Brain development is a complex process that requires the production and differentiation of numerous cells and cell types, with the additional challenge of spatial and temporal precision in the neural circuitry that connects these cells. Improper formation of neural circuitry leads to impaired control over brain activity patterns and is broadly thought to contribute to a number of childhood neurological disorders. Multiple lines of research suggest that inhibitory GABAergic circuitry in particular contributes to the pathophysiology of neurodevelopmental disorders, yet symptoms of intellectual disability (ID), and epilepsy common in these disorders remain poorly treated. Our prior work has identified the GABAA receptor α2 subunit as central to human ID syndromes caused by mutations in genes known as ARHGEF9 and NONO. We have found that impairments in α2 expression and localization lead to impaired specification of subtypes of inhibitory synapses in models replicating features of human syndromic ID. In studying these models, we also identified abnormalities in cortical cell morphology and cortical organization suggestive of dysfunction in earlier developmental processes. A role for the GABAA receptor α2 subunit in early developmental stages is further supported by its notably high level of expression in early neurodevelopment, well before synapses are formed. On this premise, we hypothesize that both early trophic signaling and later synaptic signaling via the GABAAR α2 subunit are necessary for typical cortical development, with dysfunction in each contributing to distinct phenotypic features of ID syndromes. In this proposal we will manipulate either the GABAA α2 subunit (aim 1), ARHGEF9 (aim 2), or NONO (aim 3) and examine: (i.) early developmental stages of process outgrowth, neuron polarization, and spine formation in vitro, as well as (ii.) tissue level features such as cortical organization, cell morphology, and synapse specification in vivo. These complementary approaches are expected to provide comprehensive information about the mechanisms of discrete but interdependent developmental processes necessary for typical cortical development, with implications for non-typical cortical development seen in neurodevelopmental disorders. Relevance to human health: The proposed project is expected to yield detailed information about neurodevelopmental stages ranging from process outgrowth to synapse formation and specification in both typical and non-typical conditions, providing both basic knowledge about brain development, and translational insights for neurodevelopmental disorders. Outcomes: This rigorous and impactful work will be conducted entirely by undergraduate and graduate students at UNLV, which is one of the nation’s most diverse campuses. Thus, beyond scientific outcomes, this project will provide instrumental training opportunities for the diversification of the biomedical workforce, as well as enhance the research environment of our institution.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
