Showing papers by "Stephen J. Smith published in 2013"
TL;DR: A novel role for astrocytes in mediating synapse elimination in the developing and adult brain is revealed, MEGF10 and MERTK are identified 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.
Abstract: 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.
919 citations
TL;DR: The results suggest that ephrin-A2 regulates experience-dependent, NMDA receptor-mediated synaptic pruning through glial glutamate transport during maturation of the mouse cortex.
46 citations
TL;DR: This work presents an automated feature extraction and classification algorithm designed to quantify synapses from high-dimensional array tomographic data too voluminous for manual analysis, and uses it to quantify laminar distributions of synapses in mouse somatosensory cortex.
Abstract: Synapses of the mammalian central nervous system are highly diverse in function and molecular composition. Synapse diversity per se may be critical to brain function, since memory and homeostatic mechanisms are thought to be rooted primarily in activity-dependent plastic changes in specific subsets of individual synapses. Unfortunately, the measurement of synapse diversity has been restricted by the limitations of methods capable of measuring synapse properties at the level of individual synapses. Array tomography is a new high-resolution, high-throughput proteomic imaging method that has the potential to advance the measurement of unit-level synapse diversity across large and diverse synapse populations. Here we present an automated feature extraction and classification algorithm designed to quantify synapses from high-dimensional array tomographic data too voluminous for manual analysis. We demonstrate the use of this method to quantify laminar distributions of synapses in mouse somatosensory cortex and validate the classification process by detecting the presence of known but uncommon proteomic profiles. Such classification and quantification will be highly useful in identifying specific subpopulations of synapses exhibiting plasticity in response to perturbations from the environment or the sensory periphery.
35 citations