Excitatory spinogenesis (dendritic spine formation) is a key neurodevelopmental process that begins with filopodia formation, leads to axonal contact, spine maturation, recruitment of AMPA type glutamate receptors, and functional synapse formation. Later, in adulthood, actin-rich spine synapses undergo both rapid changes in morphology as well as slower alterations in spine turnover that are associated with experience and are thought to encode long-term modifications in neural network connectivity. However, the underlying mechanisms and regulation of these stages of spine regulation are poorly understood. This proposal will test the role of Arp2/3, a critical activator of actin polymerization, in these developmental milestones and experience driven processes. It will also determine how its activity may be fine-tuned during these processes. This will be accomplished by using two new lines of conditional knockout mice in combination with electrophysiology and in vivo imaging of spine development and plasticity. Overall, the anticipated results of this study will significantly enhance our understanding of dendritic filopodia initiation, maturation, and plasticity. As many child and adult onset brain disorders, including autism, intellectual disability, schizophrenia, Alzheimer's Disease, and epilepsy are associated with abnormal spine synapses, these results can be expected to lead to new insights into potential etiologies associated with these disorders.
Using unique genetic tools for cytoskeletal manipulation in vivo, this project will address fundamental questions regarding the mechanisms underlying the formation, maturation, and plasticity of dendritic spines. Answering these key questions can be expected to facilitate novel future directions for the prevention and possible treatment of neurodevelopmental disorders such as intellectual disability and autism. Understanding the neurobiology underlying the onset and progression of developmental disorders is highly relevant to the mission of the NIH.
| Spence, Erin F; Kanak, Daniel J; Carlson, Benjamin R et al. (2016) The Arp2/3 Complex Is Essential for Distinct Stages of Spine Synapse Maturation, Including Synapse Unsilencing. J Neurosci 36:9696-709 |
| Spence, Erin F; Soderling, Scott H (2015) Actin Out: Regulation of the Synaptic Cytoskeleton. J Biol Chem 290:28613-22 |
