Honors & Awards
Postdoctoral Fellowship, Damon Runyon Cancer Research Foundation (2009-2012)
Doctor of Philosophy, University of California San Francisco (2009)
Ben Barres, Postdoctoral Faculty Sponsor
Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways
2013; 504 (7480): 394-?
To achieve its precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodelling. Recently, microglial cells have been shown to be responsible for a portion of synaptic pruning, but the remaining mechanisms remain unknown. Here we report a new role for astrocytes in actively engulfing central nervous system synapses. This process helps to mediate synapse elimination, requires the MEGF10 and MERTK phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways fail to refine their retinogeniculate connections normally and retain excess functional synapses. Finally, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. These studies reveal a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, identify MEGF10 and MERTK as critical proteins in the synapse remodelling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes.
View details for DOI 10.1038/nature12776
View details for Web of Science ID 000328575300043
View details for PubMedID 24270812
The role of glial cells in synapse elimination
CURRENT OPINION IN NEUROBIOLOGY
2012; 22 (3): 438-445
Excessive synapses generated during early development are eliminated extensively to form functionally mature neural circuits. Synapses in juvenile and mature brains are highly dynamic, and undergo remodeling processes through constant formation and elimination of dendritic spines. Although neural activity has been implicated in initiating the synapse elimination process cell-autonomously, the cellular and molecular mechanisms that transduce changes in correlated neural activity into structural changes in synapses are largely unknown. Recently, however, new findings provide evidence that in different species, glial cells, non-neuronal cell types in the nervous system are crucial in eliminating neural debris and unwanted synapses through phagocytosis. Glial cells not only clear fragmented axons and synaptic debris produced during synapse elimination, but also engulf unwanted synapses thereby actively promoting synapse elimination non-cell autonomously. These new findings support the important role of glial cells in the formation and maintenance of functional neural circuits in development as well as in adult stages and neurodegenerative diseases.
View details for DOI 10.1016/j.conb.2011.10.003
View details for Web of Science ID 000306634700011
View details for PubMedID 22036016
Development of a Method for the Purification and Culture of Rodent Astrocytes
2011; 71 (5): 799-811
The inability to purify and culture astrocytes has long hindered studies of their function. Whereas astrocyte progenitor cells can be cultured from neonatal brain, culture of mature astrocytes from postnatal brain has not been possible. Here, we report a new method to prospectively purify astrocytes by immunopanning. These astrocytes undergo apoptosis in culture, but vascular cells and HBEGF promote their survival in serum-free culture. We found that some developing astrocytes normally undergo apoptosis in vivo and that the vast majority of astrocytes contact blood vessels, suggesting that astrocytes are matched to blood vessels by competing for vascular-derived trophic factors such as HBEGF. Compared to traditional astrocyte cultures, the gene profiles of the cultured purified postnatal astrocytes much more closely resemble those of in vivo astrocytes. Although these astrocytes strongly promote synapse formation and function, they do not secrete glutamate in response to stimulation.
View details for DOI 10.1016/j.neuron.2011.07.022
View details for Web of Science ID 000294877900006
View details for PubMedID 21903074
Selective Remodeling: Refining Neural Connectivity at the Neuromuscular Junction
2009; 7 (8)
A primer on new research by Fuentes-Medel and colleagues explains the important role of non-neural cells in clearing neural debris, which is continuously produced during the normal remodeling processes that establish and maintain neural connectivity.
View details for DOI 10.1371/journal.pbio.1000185
View details for Web of Science ID 000269226300004
View details for PubMedID 19707269