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Favuzzi E, Huang S, Saldi GA, Binan L, Ibrahim LA, Fernández-Otero M, Cao Y, Zeine A, Sefah A, Zheng K, Xu Q, Khlestova E, Farhi SL, Bonneau R, Datta SR, Stevens B, Fishell G. GABA-receptive microglia selectively sculpt developing inhibitory circuits. Cell. 2021 Jul 22;184(15):4048-4063.e32. Epub 2021 Jul 6 PubMed. Correction.
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University of Cambridge
The papers by Cao et al. and Venturino et al. are important in that they significantly extend the array of conditions under which microglia that modify synaptic plasticity induced by neuronal signals can be studied in the adult mouse brain. The peri-synaptic ECM in the round takes the center stage, a component that has been thrown into prominence recently after an interlude of neglect (Nguyen et al., 2020; Crapser et al., 2020; Duncan et al., 2019; Fawcett et al., 2019). Favuzzi et al. add yet a third signaling mechanism that accounts for the sculpting of inhibitory synapses by microglia during development.
The significant question these studies raise is whether the same fundamental mechanisms underpin each system despite their diversity of origin and outcomes (detrimental in the case of early inflammation, beneficial in the case of restoring ocular-dominance plasticity in the adult or GABAergic-dependent behavior). There may be specialized microglia devoted to synaptic plasticity remodeling in each situation, although microglia defined by transcriptomics are reported to be essentially uniform in the healthy adult mouse brain.
Interestingly, there is a bias in two of the studies toward effects in male participants.
Another question is whether the same mechanisms and types of neuron/microglia cross talk occur in the human brain, bearing in mind the restricted environment to which mice are exposed during their lifetime compared with the diversity of human experience. These questions can only be addressed once the causal molecular players have been defined, several of which are newly proposed in these papers.
References:
Nguyen PT, Dorman LC, Pan S, Vainchtein ID, Han RT, Nakao-Inoue H, Taloma SE, Barron JJ, Molofsky AB, Kheirbek MA, Molofsky AV. Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity. Cell. 2020 Jul 23;182(2):388-403.e15. Epub 2020 Jul 1 PubMed.
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View all comments by Aviva TolkovskyUniversity College London
University College London
In this interesting study, Venturino et al. show that modulating gamma oscillations in the brain with low doses of ketamine, or exposing the mice to 60 Hz flickering light, triggers microglial engulfment of perineuronal nets (PNNs) and thus enables the formation of new synapses.
Microglia interact with neurons to promote not just phagocytic removal of synapses (Paolicelli et al., 2011; Schafer et al., 2012) but also formation of synapses: microglial contacts with neurons lead to formation of filopodia and dendritic spines in the hippocampus (Weinhard et al., 2018) and cortex (Miyamoto et al., 2016).
Venturino et al. add to recent research showing that synapse formation may also be promoted by enhancing phagocytic clearing of the extracellular matrix in which neurons are embedded (which creates space for new synapses: Nguyen et al., 2020). Clearing this matrix may also facilitate microglial removal of synapses, because phagocytosis relies on close-proximity interaction with membrane receptors, which can be impeded by physical barriers such as the glycocalyx surrounding the cell membrane (Imbert et al., 2021).
P2Y12 receptors are critical to attract microglia to neuronal somata in the cortex (Cserép et al., 2020) but also regulate microglia-mediated engulfment of synapses (Sipe et al., 2016) and of myelinated axons (Maeda et al., 2010). Activation of P2Y12 receptors triggers chemotaxis to damaged cells (Haynes et al., 2006) and perhaps active synapses, and promotes interactions with the extracellular matrix via β-integrins (Ohsawa et al., 2010). Venturino et al. expand on these data, by showing that P2Y12 receptor block prevents the light-flicker-induced degradation of PNNs by microglia. Future work could examine whether downstream activation of THIK-1 (Madry et al., 2018) may underlie some of these effects, as suggested by recent work (Izquierdo et al., 2021).
PNNs predominantly surround PV inhibitory interneurons, which act as a pacemaker for gamma oscillations (a type of neuronal network activity), and PNN removal is known to decrease inhibition, increase synaptic plasticity, and increase gamma oscillations (Lensjø et al., 2017). Gamma oscillations are important because they contribute to higher cognitive functions such as attention and memory (Gregoriou et al., 2009; Fries et al., 2001; Pesaran et al., 2002). In the healthy brain, when PNNs are removed either pharmacologically or by microglial engulfment, the neuronal network activity returns to its immature state (with a variable gamma oscillation pattern), allowing room for new synapse formation (see review: Fawcett et al., 2019). Indeed, Venturino et al. found that simulated gamma oscillations induced microglial interactions with PV interneurons and removed PNNs, allowing synapse growth.
Synapse formation and elimination occur throughout life, but are more pronounced in younger animals. Thus, microglial modulation might be more effective in affecting synapse numbers in early life. However, microglial functions that occur during development (including the remodeling of synapses) can be re‑engaged in the diseased brain, for example in Alzheimer’s disease (but not in schizophrenia: Tzioras et al., 2020). Previously, flickering light, mimicking gamma oscillations, was shown to induce microglial morphological changes to enhance engulfment of extracellular material, such as toxic Aβ (Iaccarino et al., 2016), aiding in the prevention of unwanted pathophysiology. This offers an attractive therapeutic potential for neurological disorders with abnormal clearance of substances such as Aβ.
Unfortunately, however, removing PNNs isn’t a magical solution to devastating neurological disorders. Although PNN loss in the healthy brain is suggestive of returning to a more plastic “juvenile” state, allowing new synapse formation, PNN removal by microglia is also observed in Alzheimer’s disease (Crapser et al., 2020). Thus, there may be a fine balance between retaining PNNs to protect neurons from toxic substances and removing them to create space for synaptic growth.
References:
Crapser JD, Spangenberg EE, Barahona RA, Arreola MA, Hohsfield LA, Green KN. Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain. EBioMedicine. 2020 Aug;58:102919. Epub 2020 Jul 31 PubMed.
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Imbert PR, Saric A, Pedram K, Bertozzi CR, Grinstein S, Freeman SA. An Acquired and Endogenous Glycocalyx Forms a Bidirectional "Don't Eat" and "Don't Eat Me" Barrier to Phagocytosis. Curr Biol. 2021 Jan 11;31(1):77-89.e5. Epub 2020 Oct 22 PubMed.
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