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Microglia contact induces synapse formation in developing somatosensory cortex.

ABSTRACT: Microglia are the immune cells of the central nervous system that play important roles in brain pathologies. Microglia also help shape neuronal circuits during development, via phagocytosing weak synapses and regulating neurogenesis. Using in vivo multiphoton imaging of layer 2/3 pyramidal neurons in the developing somatosensory cortex, we demonstrate here that microglial contact with dendrites directly induces filopodia formation. This filopodia formation occurs only around postnatal day 8-10, a period of intense synaptogenesis and when microglia have an activated phenotype. Filopodia formation is preceded by contact-induced Ca(2+) transients and actin accumulation. Inhibition of microglia by genetic ablation decreases subsequent spine density, functional excitatory synapses and reduces the relative connectivity from layer 4 neurons. Our data provide the direct demonstration of microglial-induced spine formation and provide further insights into immune system regulation of neuronal circuit development, with potential implications for developmental disorders of immune and brain dysfunction.

SUBMITTER: Miyamoto A

PROVIDER: S-EPMC5007295 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Microglia contact induces synapse formation in developing somatosensory cortex.

Miyamoto Akiko A Wake Hiroaki H Ishikawa Ayako Wendy AW Eto Kei K Shibata Keisuke K Murakoshi Hideji H Koizumi Schuichi S Moorhouse Andrew J AJ Yoshimura Yumiko Y Nabekura Junichi J

Nature communications 20160825

Microglia are the immune cells of the central nervous system that play important roles in brain pathologies. Microglia also help shape neuronal circuits during development, via phagocytosing weak synapses and regulating neurogenesis. Using in vivo multiphoton imaging of layer 2/3 pyramidal neurons in the developing somatosensory cortex, we demonstrate here that microglial contact with dendrites directly induces filopodia formation. This filopodia formation occurs only around postnatal day 8-10, ...[more]

PMID: 27558646

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Project description:UnlabelledRapid HIV-1 spread between CD4 T lymphocytes occurs at retrovirus-induced immune cell contacts called virological synapses (VS). VS are associated with striking T cell polarization and localized virus budding at the site of contact that facilitates cell-cell spread. In addition to this, spatial clustering of organelles, including mitochondria, to the contact zone has been previously shown. However, whether cell-cell contact specifically induces dynamic T cell remodeling during VS formation and what regulates this process remain unclear. Here, we report that contact between an HIV-1-infected T cell and an uninfected target T cell specifically triggers polarization of mitochondria concomitant with recruitment of the major HIV-1 structural protein Gag to the site of cell-cell contact. Using fixed and live-cell imaging, we show that mitochondrial and Gag polarization in HIV-1-infected T cells occurs within minutes of contact with target T cells, requires the formation of stable cell-cell contacts, and is an active, calcium-dependent process. We also find that perturbation of mitochondrial polarization impairs cell-cell spread of HIV-1 at the VS. Taken together, these data suggest that HIV-1-infected T cells are able to sense and respond to contact with susceptible target cells and undergo dynamic cytoplasmic remodeling to create a synaptic environment that supports efficient HIV-1 VS formation between CD4 T lymphocytes.ImportanceHIV-1 remains one of the major global health challenges of modern times. The capacity of HIV-1 to cause disease depends on the virus's ability to spread between immune cells, most notably CD4 T lymphocytes. Cell-cell transmission is the most efficient way of HIV-1 spread and occurs at the virological synapse (VS). The VS forms at the site of contact between an infected cell and an uninfected cell and is characterized by polarized assembly and budding of virions and clustering of cellular organelles, including mitochondria. Here, we show that cell-cell contact induces rapid recruitment of mitochondria to the contact site and that this supports efficient VS formation and consequently cell-cell spread. Additionally, we observed that cell-cell contact induces a mitochondrion-dependent increase in intracellular calcium, indicative of cellular signaling. Taken together, our data suggest that VS formation is a regulated process and thus a potential target to block HIV-1 cell-cell spread.

Project description:Layer 1 of the neocortex is sparsely populated with neurons and heavily innervated by fibers from lower layers and proximal and distal brain regions. Understanding the potential functions of this layer requires a comprehensive understanding of its cellular and synaptic organization. We therefore performed a quantitative study of the microcircuitry of neocortical layer 1 (L1) in the somatosensory cortex in juvenile rats (P13-P16) using multi-neuron patch-clamp and 3D morphology reconstructions. Expert-based subjective classification of the morphologies of the recorded L1 neurons suggest 6 morphological classes: (1) the Neurogliaform cells with dense axonal arborizations (NGC-DA) and with sparse arborizations (NGC-SA), (2) the Horizontal Axon Cell (HAC), (3) those with descending axonal collaterals (DAC), (4) the large axon cell (LAC), and (5) the small axon cell (SAC). Objective, supervised and unsupervised cluster analyses confirmed DAC, HAC, LAC and NGC as distinct morphological classes. The neurons were also classified into 5 electrophysiological types based on the Petilla convention; classical non-adapting (cNAC), burst non-adapting (bNAC), classical adapting (cAC), classical stuttering (cSTUT), and classical irregular spiking (cIR). The most common electrophysiological type of neuron was the cNAC type (40%) and the most common morpho-electrical type was the NGC-DA-cNAC. Paired patch-clamp recordings revealed that the neurons were connected via GABAergic inhibitory synaptic connections with a 7.9% connection probability and via gap junctions with a 5.2% connection probability. Most synaptic connections were mediated by both GABAA and GABAB receptors (62.6%). A smaller fraction of synaptic connections were mediated exclusively by GABAA (15.4%) or GABAB (21.8%) receptors. Morphological 3D reconstruction of synaptic connected pairs of L1 neurons revealed multi-synapse connections with an average of 9 putative synapses per connection. These putative synapses were widely distributed with 39% on somata and 61% on dendrites. We also discuss the functional implications of this L1 cellular and synaptic organization in neocortical information processing.

Dataset Information

Microglia contact induces synapse formation in developing somatosensory cortex.

Publications

Microglia contact induces synapse formation in developing somatosensory cortex.

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