New Function of Microglia: Promotion of Filopodia and Hence Synaptogenesis during Early Brain Development

Promotion of Filopodia - Synaptogenesis
Promotion of Filopodia – Synaptogenesis

A recent study published in Nature Communications reveals that the brain microglia influences the developing brain through induction of filopodia creation, thus, shaping neuronal connectivity and synapses formation.

Increasing evidences point to the important influence immune status and immune molecules have on brain development and function. Maternal infection is a considerable risk factor for the neurodevelopmental disorders such as autism and schizophrenia.

Microglia  are important components of the neuro-immune interactions in the brain and defects in microglial genes or signalling molecules are associated with disorders of neuronal circuits and brain behaviour. As the resident macrophage cells, the microglial cells provide the main immune defense in the central nervous system.

As the immune cells of the central nervous system, microglia respond to various brain pathologies, adopt an activated phenotype and secrete a range of cytokines and neuro-trophic factors to modify disease progression.

Synapses develop from filopodia, labile, postsynaptic protrusions that may stabilize and develop into mature spines when they connect onto presynaptic terminals. Microglia contribute to a number of aspects of neural circuit development, including to help define the neuronal population via regulation of apoptosis and neurogenesis and by phagocytosing excess synapses during synaptic pruning.

Recent evidence indicates that microglia also contributes to the normal brain physiology, including neurogenesis and the promotion of synapse formation. More recent studies have suggested microglia have bidirectional effects on synapses and neuronal circuits by promoting synapse formation.

A role for microglia in enhancing spine density has also been suggested from in vitro studies. Thus, for example, adding microglial cells to hippocampal cultures results in the increase of the number of dendritic spines, an effect mediated via the release of interleukin (IL) -10.

Release of cytokines such as IL-10 by microglia is typically associated with an activated microglia phenotype, such as occurs when microglia begin to populate the cortex during early postnatal development. However, (1) how microglia may contribute to functional synapse formation; (2) whether this is a direct result of microglia–neuron interactions; and (3) the functional significance of putative microglia-induced spine formation in development is all unclear.

Little is known, however, how, in fact, microglia trigger or modify synapse formation, and whether this effect is directly dependent on microglia-neurons interactions.

In the Nature Communications report, Akiko Miyamoto and colleagues, provided a direct demonstration of how microglia-neuronal interactions can shape neuronal morphology and connectivity, via the induction of filopodia formation.

Of note, synapses develop from filopodia that according to the authors represent “labile, postsynaptic protrusions that may stabilize and develop into mature spines” (cf. Refs. 22, 25, 34 and 35, the Miyamoto et al. study).

Using in vivo multiphoton imaging of layer 2/3 pyramidal neurons in the developing somatosensory cortex in mice, the authors report that the direct contact between microglia and dendrites induced a rapid appearance and growth of filopodia, through Ca2+ accumulation and actin recruitment. Moreover, blocking microglia activity caused fewer functional synapses formation and less dendritic arborization.

Importantly, the authors observed that this microglia contact-induced filopodia was only observed at the 8th to 10th days, corresponding to an ameboid-like microglia (activated state), which can involve the release of soluble factors such as IL-10, tumor necrosis factor (TNF)-α and nerve growth factors.

Thus, it appears that Miyamoto et al. provide the first evidence that the microglia contact induces filopodia and, then, synapses formation, revealing a new physiologic function for microglia.

The authors suggest that “filopodia formation by microglia promotes the maturation of specific neuronal circuit connections through the formation of functional mature synapses”.

They also believe that these mechanisms may also contribute to psychiatric disorders, such as schizophrenia and autism where “disruptions in synapse number, morphology or function” are reported.

In summary, this study demonstrates a new physiological role for microglia in promoting synapses during a transient period of brain development, as contacts between microglial processes and dendritic shafts could trigger filopodia formation.

Source: Nat Commun, 2016 Aug 25; 7:12540. doi: 10.1038/ncomms12540
Read More: Nature Communications

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