During the first year of my K99, I received an offer and accepted a positon as an Assistant Professor in the Neurobiology Department at the University of Massachusetts Medical School. As a result, I am applying for transition to the ROO phase where I will be investigating microglia-specific mechanisms driving activity-dependent synaptic remodeling in the developing brain. The ultimate goal is to apply these mechanisms to neurodevelopmental and neuropsychiatric disorders. Immature synapses form a crude wiring diagram that must remodel during development to achieve the precise connectivity characteristic of the mature nervous system. While It is clear that neural activity drives synaptic remodeling, the underlying mechanisms are not fully understood. We recently identified that microglia participate in synaptic remodeling by engulfing synaptic elements in an activity-dependent manner. However, it is unknown whether microglia engulf intact synapses or whether this is a non-cell autonomous event. In addition, it is known that microglia change their motility and interactions with synapse in response to neural activity but the underlying molecular mechanisms and functional consequences of these responses are unknown. As a result the goals of this proposal are to: 1) Aimi: Test the hypothesis that microglia are actively sensing, interacting with, and phagocytosing intact synapses in response to changes in neural activity. The laboratory is uniquely positioned to address this question with expertise in imaging microglia by 2-photon In vivo live Imaging, a skill acquired during the K99 phase. 2) Aim 2: Dissect the molecular mechanisms underlying microglia responses to changes in neural activity. A number of candidate microglia-specific molecules and cytokines have been identified and validated, including IL-12. Thus, activity-dependent microglia motility and interactions with synapses will be assessed In mice deficient in genes of interest. 3) Aim 3: Determine the functional significance of activity-dependent microglial responses by testing the hypothesis that these responses regulate the development of synaptic circuit structure and function in mice with deficiencies in genes previously identified and validated.
Aberrant synaptic circuits and microglial dysfunction are now recognized as hallmarks of several neurodevelopmental and psychiatric disorders (e.g. autism, schizophrenia, etc.). Thus, long-term goals of this research will be to understand how glial cells contribute to circuit abnormalities underlying these disorders. This research will offer Insight into mechanisms and biomarkers of disease as well as potential for development of novel therapeutic strategies.
|Werneburg, Sebastian; Feinberg, Philip A; Johnson, Kasey M et al. (2017) A microglia-cytokine axis to modulate synaptic connectivity and function. Curr Opin Neurobiol 47:138-145|
|Schafer, Dorothy P; Heller, Christopher T; Gunner, Georgia et al. (2016) Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression. Elife 5:|
|Frost, Jeffrey L; Schafer, Dorothy P (2016) Microglia: Architects of the Developing Nervous System. Trends Cell Biol 26:587-97|