Not Just Alzheimer's: Microglia Sculpt the Brain in Health and Disease

Series - Microglia in Health and Disease:

Part 2 of 2
Judging by recent coverage on this site, Alzforum readers might be forgiven for thinking all microglia do is act prominently, if mysteriously, in Alzheimer's disease pathogenesis (see Part 1 of this series). Not so. Recent research has raised the profile of microglia overall, promoting them from garbage disposal crew to active sculptors of neuronal circuitry. Some basic biological functions coming to light now may become relevant to conditions as common as depression or post-traumatic stress disorder (PTSD).

  • A specialized microglial subtype prunes inhibitory synapses.
  • Microglia chew up extracellular matrix in adult brain, making room for plasticity.
  • Infections prime microglia to overreact to later stress and devour synapses.

Most recently, three new mouse studies shed light on how microglia prune synaptic connections during development, and how the same process can reawaken later in life—for good or ill. One study identified a subtype of microglia that express the GABAB receptor and trim inhibitory synapses. Such neuron-glia matching hints that their interactions may be as selective as neuron-to-neuron connections. Another paper describes how microglia can revive developmental plasticity: Stimulating the adult brain with the anesthetic ketamine or with flashing lights triggered microglia to chew up the extracellular matrix around interneurons. This created space that fresh synaptic spines then filled. Such a process might help the brain overcome negative experiences in PTSD or depression, and possibly even foreshadow microglial mechanisms underpinning the renewed interest in clinical trials of psychedelic drugs.

To be sure, stimulating microglia’s appetite can harm the brain, too. In the third study, systemic inflammation in youth somehow “stamped” microglia, priming them to over-prune synapses when the mice experienced stress later in life. This finding may help scientists elucidate how early life stress leaves the brain vulnerable to later neuropsychiatric disorders.

“These three studies add to the understanding of the essential functions of microglia in disease and neural plasticity, and they offer new information about specific mechanisms of action,” Douglas Fields at the National Institute of Child Health and Human Development in Bethesda, Maryland, wrote to Alzforum. Aviva Tolkovsky at the University of Cambridge, U.K., wondered whether the same fundamental mechanisms underpin each system. And would these be conserved in human brain? “These questions can only be addressed once the causal molecular players have been defined, several of which are newly proposed in these papers,” Tolkovsky wrote to Alzforum (full comment below).

Specialized Destruction: GABA Links Microglial Type to Inhibitory Synapses
Pioneering work from the late Ben Barres’ group at Stanford University first implicated astrocytes and microglia in synapse formation and maintenance, then found that synaptic pruning involved complement proteins of the innate immune system (Jan 2001 news; Dec 2007 news; Mar 2015 conference news). Microglia also devour synapses in response to environmental conditions, and in neurodegenerative disease (Nov 2010 news; Nov 2015 conference news; Oct 2019 news). 

Picky Eater. GABAB receptor-expressing microglia (green) contain within them synapses (red) from inhibitory neurons. [Courtesy of Favuzzi et al., Cell.]

But how selective is this pruning? In the July 22 Cell, researchers led by Gord Fishell at Harvard Medical School revealed that microglia have a discerning palate for the synapses they eat. First author Emilia Favuzzi began by asking whether microglia could tell the difference between inhibitory and excitatory synapses. Inhibitory synapses respond to GABA, the brain’s premier inhibitory neurotransmitter (Shaye et al., 2021). Working with Fishell and Beth Stevens at Boston Children’s Hospital, Favuzzi fluorescently labeled inhibitory synapses in the somatosensory cortices of newborn mice and characterized the microglia that later engulfed them (see image above).

Surprisingly, perhaps, these microglia expressed the GABAB receptor, and they ignored excitatory synapses. They made up a quarter of all microglia in the region. Knocking out the GABAB receptor only in microglia produced a glut of inhibitory synapses by two weeks of age, but no change in excitatory synapses.

How would the GABAB receptor promote removal of inhibitory synapses? Partly by revving up the requisite machinery. Single-cell RNA-Seq showed that microglia lacking this receptor dampened expression of genes needed for synaptic pruning. This includes the complement protein C1q, which tags synapses for elimination. However, the scientists do not know how the system selects which inhibitory synapses to snip. Normal developmental pruning eliminates weaker, i.e., less active, synapses. “It’s counterintuitive, because GABA is the sign of a well-working synapse, yet it recruits microglia to prune synapses,” Fishell noted.

Curiously, though the GABAB receptor knockout mice had more inhibitory synapses than did wild-types at 2 weeks of age, by 2 months they had fewer. Mouse behavior reflected this, as seen by motion sequencing, a behavioral measure developed by co-author Sandeep Datta at Harvard. In this method, researchers film mice for an hour, tallying their different motions to develop fine-grained signatures of behavior. The 2-week-old knockouts were less active than wild-types, but by 2 months, they had become hyperactive. The data suggest a compensatory mechanism kicks in to offset the excess inhibition.

In future work, Favuzzi will delve into the mechanism behind inhibitory synapse pruning, and also search for microglial subtypes specialized to remove other types of synapses. Many neuropsychiatric disorders, including schizophrenia and autism, are marked by imbalances between excitatory and inhibitory synapses. If science could harness the brain’s immune system to restore this balance, it might help correct such disorders, Fishell suggested.

Gek-Ming Sia at the University of Texas, San Antonio, agreed this has potential. “This important work elegantly demonstrates a new idea. It opens up the intriguing possibility that modulation of microglia may be used to selectively tune specific synapses in a neural circuit to achieve a behavioral effect,” Sia wrote to Alzforum.

Siccing Microglia on Extracellular Matrix Unlocks Plasticity
Paring back synapses is a normal part of sculpting circuitry, but what about enabling new synapses to grow? Microglia apparently can do this, too. Previous research has shown that microglia need to be present for adult mice to learn new behaviors (Dec 2013 news). Microglia promote learning by trimming away extracellular matrix to allow new synapses to form (Jul 2020 news). 

Vanishing Act. The perineuronal net (black) around interneurons in somatosensory cortex is thick under normal conditions (left), thinner after two ketamine treatments (middle), and gone after three (right). [Courtesy of Venturino et al., Cell Reports.]

In the July 6 Cell Reports, researchers led by Sandra Siegert at the Institute of Science and Technology in Klosterneuburg, Austria, focused on the role of the perineuronal net. The PNN is a sugary web that enmeshes parvalbumin-positive GABAergic interneurons; it constitutes one of the “tougher” parts of the extracellular matrix. The PNN locks synaptic circuitry into place (Pizzorusso et al., 2002; Frischknecht and Gundelfinger, 2012; Lensjø et al., 2017). 

Enzymatic dissolution of the PNN is known to reactivate plasticity (Mar 2013 conference news), but Siegert wanted to experiment with the PNN in ways that are less destructive to the brain. She was intrigued by reports that low doses of the anesthetic ketamine, given to rats to induce schizophrenia-like brain changes, also thinned out the PNN (Matuszko et al., 2017; Kaushik et al., 2021). 

To explore how this might work, first author Alessandro Venturino treated adult wild-type mice with high-dose ketamine. Three treatments completely abolished the PNN in the somatosensory and visual cortex (see image above). The strength of the effect was surprising, Siegert noted. “It’s rare in science that you see such a black-and-white phenotype,” she told Alzforum. As expected, removal of the PNN enabled new synapses to grow. When the scientists covered one of the animal’s eyes after PNN clearance, neurons connected to the open eye fired more, indicating synapse formation.

Importantly, the researchers traced the vanishing PNN to microglia. After ketamine exposure, microglia sidled up to interneurons and released matrix metalloprotease 9, an enzyme that degrades PNN. Chunks of the material appeared inside microglial lysosomes. By contrast, when microglia were depleted from mouse brain prior to ketamine exposure, the PNN stayed put.

The findings are evocative of the recent explosion of interest in ketamine as a potential treatment for conditions such as intractable depression, PTSD, and chronic pain (Carboni et al., 2021; Liriano et al., 2019; Cohen et al., 2018). Low-dose ketamine in the form of a nasal spray has been approved by the FDA to treat depression. Ketamine’s benefits are usually ascribed to its ability to block NMDA signaling, but the new data strengthen the idea that it may act by stimulating new synapse growth, as well (Krystal et al., 2017). That said, ketamine also has serious negative effects, including transient schizophrenia-like symptoms, sedation, and disordered thinking; its use must be carefully monitored.

How else could microglia be prodded to mow the PNN lawn? Ketamine is known to alter brain network activity, strengthening gamma frequency oscillations (Pinault, 2008; Ahnaou et al., 2017; Castro-Zaballa et al., 2018). To see if directly modulating gamma activity could produce the same effect, the researchers shined flickering lights into the eyes of mice. Lights flickering at 60 Hz, but not 40 Hz, slashed the amount of PNN in visual cortex by nearly half. Removing microglia before light exposure prevented this, demonstrating that these cells were responsible.

Microglia are known to monitor neuronal activity via P2Y12, a G-protein coupled purinergic receptor, or GCPR, on the microglial cell membrane. P2Y12 senses the ATP/ADP energy balance given off by neuronal cell bodies (Dec 2019 news). In this new study, blocking P2Y12 kept the PNN in place after 60 Hz treatment, again identifying neuronal activity as the key mediator of this microglial response. It appears that changes in the neuron’s energy level can ring the alarm bell for microglia, triggering them to “shave” the PNN and permit new synapse growth.

Curiously, 40 Hz light, which did not affect PNN in this study, has been reported to induce microglia to gobble up amyloid plaques and is currently in trials for Alzheimer’s disease (Dec 2016 news; May 2019 news; Apr 2021 conference news). The data suggest microglia and neuronal circuits interact in sophisticated ways, Siegert said, whereby different frequencies might elicit different reactions.

Fields agreed that microglia are sensitive to the frequency of brainwave oscillations and will intervene to restore normal neural activity patterns. “Therapeutic applications that exploit the involvement of microglia in regulating excitability of neural circuits may be possible, but much more research is needed,” he wrote to Alzforum. Siegert speculated that, like ketamine, PNN removal by light treatment eventually could be harnessed to treat neuropsychiatric conditions such as PTSD or depression. Both safety and efficacy of either ketamine or light treatment require further study.

David Attwell, Pablo Izquierdo, and Hiroko Shiina at University College, London, noted that the P2Y12 receptor facilitates synapse elimination, too. Removing the PNN may aid microglia in this endeavor, because stripping away the sugary “beard” enables microglial processes to contact neuronal membrane more easily (Sipe et al., 2016; Imbert et al., 2021). “Removing PNNs isn’t a magical solution to devastating neurological disorders … there may be a fine balance between retaining PNNs to protect neurons from toxic substances, and removing them to create space for synaptic growth,” they cautioned (full comment below).

Microglia were recently reported to chew up PNN in Alzheimer’s disease, both in a mouse model and in human brain tissue (Crapser et al., 2020). 

Ádám Dénes, Institute of Experimental Medicine, Budapest, Hungary, pointed out that P2Y12 mediates different microglial actions depending on whether the receptor contacts the neuronal cell body or its dendrites (Cserép et al., 2020). “We assume that microglia-PNN interactions may also be, to some extent, different in different cellular compartments,” Dénes wrote to Alzforum. “Untangling the molecular mechanisms of compartment-specific microglia-neuron interactions may be vital to understand how exactly microglia-mediated effects operate under physiological conditions and in brain diseases.”

Microglia, the Culprit in the Two-Hit Hypothesis
Not to get carried away by microglia’s benefits, these cells can clearly wreak havoc in the brain. Some scientists believe microglia mediate the “two-hit hypothesis” of neuropsychiatric disorders, whereby inflammation early in life leaves the brain prone to depression or schizophrenia during stressful experiences years later (Maynard et al., 2001; Giovanoli et al., 2016; Mottahedin et al., 2017). 

In the August 18 Neuron, researchers led by Zhi Zhang at the University of Science and Technology in Hefei, China, elaborated on this idea. Joint first authors Peng Cao, Changmao Chen, and An Liu injected lipopolysaccharide into 2-week-old, wild-type mice to trigger inflammation. At 6 weeks of age, the scientists stressed these mice in various ways, such as by restraining them, subjecting them to loud noise, or to “social defeat.” Under these pressures, LPS-injected male, though not female, mice lost their taste for sugar and gave up sooner when hung by the tail or forced to swim. These behaviors are believed to be a mouse approximation for human depression. The authors used male mice for all subsequent experiments.

After LPS, microglia in the anterior cingulate cortex became activated, as seen by stronger Iba1 staining and a more amoeboid shape. The more activated the microglia were, the more pronounced were the mouse’s later depressive-like behaviors. Depleting or inhibiting microglia before applying stress prevented these behaviors.

Lost Under Pressure. Mice subjected to LPS-induced inflammation in early life (right) lost dendritic spines after adolescent stress, while control mice (left) didn’t. [Courtesy of Cao et al., Neuron.]

As in the other studies, microglia exerted their effect by influencing synapses. Live two-photon imaging revealed microglia in the anterior cingulate cortices of LPS-treated mice swallowing glutamatergic synapses after restraint stress. The “inflamed” mice ended up with about a third fewer dendritic spines than saline-treated controls (see image at right). As might be expected, their glutamatergic neurons fired fewer action potentials. Inhibiting microglia, or activating neurons, prevented the depressive-like phenotype after stress.

LPS is known to activate toll-like receptor 4 on microglia, prompting upregulation of the fractalkine receptor CX3CR1, as well as several proinflammatory cytokines (Gan et al., 2013; Papageorgiou et al., 2016). In this study, microglia in LPS-treated mice doubled CX3CR1 expression relative to controls. This receptor is involved in synapse pruning (Paolicelli et al., 2011; Zhan et al., 2014). In keeping with this, knocking down CX3CR1 before LPS injection prevented subsequent spine loss and depressive-like behavior, while overexpressing CX3CR1 exacerbated it.

The data fit a model in which early inflammation kicks off a lasting change in microglia, causing them to express more CX3CR1. During later stress, neurons release fractalkine, which binds CX3CR1 and triggers microglia to devour spines. In this way, early life inflammation can lead to chronic maladaptation of the brain, the authors suggest.

If so, then could modulating fractalkine or its receptor become a therapeutic strategy? Fields cautioned that this system has many critical functions, so more research would be required to figure out how to tweak it safely.

Understanding what role overly active microglia and loss of spines might play in depression is a growing field (for current review, see Enomoto and Kato, 2021). Earlier this year, scientists found that the psychedelic mushroom component psilocybin helps lift depression by strengthening excitatory synapses in the hippocampus (Hesselgrave et al., 2021). Since then, Alex Kwan and colleagues at Yale University School of Medicine, New Haven, Connecticut, found that tracking the growth of new dendritic spines with two-photon microscopy enabled them to document a lasting 10 percent uptick in spine density in the frontal cortex after a single dose of psilocybin (Shao et al., 2021). Psilocybin and other psychedelics such as ketamine are being investigated for the treatment of PTSD (Krediet et al., 2020). Together, the data hint that such compounds might exert their effects by tweaking microglia’s interaction with synapses.

Kwan noted that for both ketamine and psilocybin, the issue of the best dosage to use remains underexplored. Some studies suggest that a subanesthetic dose may be most effective for boosting neural plasticity, but more work is needed. The mechanisms behind plasticity also need further elaboration. “Why there is a convergent effect for ketamine and psychedelics is still a complete mystery. Microglia could be part of the mechanism, but more work needs to be done,” Kwan wrote to Alzforum.

Siegert noted that because of the proliferation of RNA-Seq data, scientists now have more tools than ever to dissect the molecular mechanisms by which microglia affect spines and synapses and, consequently, neuronal health and behavior. “These are exciting times for the research community,” she told Alzforum.—Madolyn Bowman Rogers

Comments

  1. 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.

    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.

    Duncan JA, Foster R, Kwok JC. The potential of memory enhancement through modulation of perineuronal nets. Br J Pharmacol. 2019 Sep;176(18):3611-3621. Epub 2019 May 20 PubMed.

    Fawcett JW, Oohashi T, Pizzorusso T. The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function. Nat Rev Neurosci. 2019 Aug;20(8):451-465. Epub 2019 Jul 1 PubMed.

    View all comments by Aviva Tolkovsky

  2. 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.

    Cserép C, Pósfai B, Lénárt N, Fekete R, László ZI, Lele Z, Orsolits B, Molnár G, Heindl S, Schwarcz AD, Ujvári K, Környei Z, Tóth K, Szabadits E, Sperlágh B, Baranyi M, Csiba L, Hortobágyi T, Maglóczky Z, Martinecz B, Szabó G, Erdélyi F, Szipőcs R, Tamkun MM, Gesierich B, Duering M, Katona I, Liesz A, Tamás G, Dénes Á. Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science. 2020 Jan 31;367(6477):528-537. Epub 2019 Dec 12 PubMed.

    Fawcett JW, Oohashi T, Pizzorusso T. The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function. Nat Rev Neurosci. 2019 Aug;20(8):451-465. Epub 2019 Jul 1 PubMed.

    Fries P, Reynolds JH, Rorie AE, Desimone R. Modulation of oscillatory neuronal synchronization by selective visual attention. Science. 2001 Feb 23;291(5508):1560-3. PubMed.

    Gregoriou GG, Gotts SJ, Zhou H, Desimone R. High-frequency, long-range coupling between prefrontal and visual cortex during attention. Science. 2009 May 29;324(5931):1207-10. PubMed.

    Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci. 2006 Dec;9(12):1512-9. Epub 2006 Nov 19 PubMed.

    Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. PubMed.

    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.

    Pesaran B, Pezaris JS, Sahani M, Mitra PP, Andersen RA. Temporal structure in neuronal activity during working memory in macaque parietal cortex. Nat Neurosci. 2002 Aug;5(8):805-11. PubMed.

    Lensjø KK, Lepperød ME, Dick G, Hafting T, Fyhn M. Removal of Perineuronal Nets Unlocks Juvenile Plasticity Through Network Mechanisms of Decreased Inhibition and Increased Gamma Activity. J Neurosci. 2017 Feb 1;37(5):1269-1283. Epub 2016 Dec 30 PubMed.

    Madry C, Kyrargyri V, Arancibia-Cárcamo IL, Jolivet R, Kohsaka S, Bryan RM, Attwell D. Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1. Neuron. 2018 Jan 17;97(2):299-312.e6. Epub 2017 Dec 28 PubMed.

    Maeda M, Tsuda M, Tozaki-Saitoh H, Inoue K, Kiyama H. Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn. Glia. 2010 Nov 15;58(15):1838-46. PubMed.

    Miyamoto A, Wake H, Ishikawa AW, Eto K, Shibata K, Murakoshi H, Koizumi S, Moorhouse AJ, Yoshimura Y, Nabekura J. Microglia contact induces synapse formation in developing somatosensory cortex. Nat Commun. 2016 Aug 25;7:12540. PubMed.

    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.

    Ohsawa K, Irino Y, Sanagi T, Nakamura Y, Suzuki E, Inoue K, Kohsaka S. P2Y12 receptor-mediated integrin-beta1 activation regulates microglial process extension induced by ATP. Glia. 2010 May;58(7):790-801. PubMed.

    Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011 Sep 9;333(6048):1456-8. PubMed.

    Pesaran B, Pezaris JS, Sahani M, Mitra PP, Andersen RA. Temporal structure in neuronal activity during working memory in macaque parietal cortex. Nat Neurosci. 2002 Aug;5(8):805-11. PubMed.

    Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012 May 24;74(4):691-705. PubMed.

    Sipe GO, Lowery RL, Tremblay MÈ, Kelly EA, Lamantia CE, Majewska AK. Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat Commun. 2016 Mar 7;7:10905. PubMed.

    Tzioras M, Stevenson AJ, Boche D, Spires-Jones TL. Microglial contribution to synaptic uptake in the prefrontal cortex in schizophrenia. Neuropathol Appl Neurobiol. 2021 Feb;47(2):346-351. Epub 2020 Oct 5 PubMed.

    Venturino A, Schulz R, De Jesús-Cortés H, Maes ME, Nagy B, Reilly-Andújar F, Colombo G, Cubero RJ, Schoot Uiterkamp FE, Bear MF, Siegert S. Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain. Cell Rep. 2021 Jul 6;36(1):109313. PubMed.

    Weinhard L, di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U, Exiga M, Vadisiute A, Raggioli A, Schertel A, Schwab Y, Gross CT. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun. 2018 Mar 26;9(1):1228. PubMed.

    View all comments by David Attwell View all comments by Pablo Izquierdo View all comments by Hiroko Shiina

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. New Ways to Target TREM2 Beg the Question: Up or Down?
  2. Glia May Regulate Synaptic Formation and Transmission
  3. Paper Alert: Does the Complement Devour Synapses?
  4. Microglia Rely on Mixed Messages to Select Synapses for Destruction
  5. No Rest for Microglia: These Immune Cells Manage Healthy Synapses
  6. Microglia Control Synapse Number in Multiple Disease States
  7. Human Microglia Eat Synapses, More So in Alzheimer’s
  8. Beyond Neighborhood Watch—Microglia Nurture Synapses
  9. With IL-33, Neurons Tempt Microglia to Nibble At Synapses
  10. In Pursuit of Toxic Tau
  11. To Monitor Neurons, Microglia Talk With the Boss, aka the Soma
  12. Flashy Treatment Synchronizes Neurons, Lowers Aβ in Mice
  13. Gamma Waves Synchronized by Light: Good for Synapses, Memory?
  14. Does Synchronizing Brain Waves Bring Harmony?

Paper Citations

  1. Shaye H, Stauch B, Gati C, Cherezov V. Molecular mechanisms of metabotropic GABAB receptor function. Sci Adv. 2021 May;7(22) Print 2021 May PubMed.
  2. Pizzorusso T, Medini P, Berardi N, Chierzi S, Fawcett JW, Maffei L. Reactivation of ocular dominance plasticity in the adult visual cortex. Science. 2002 Nov 8;298(5596):1248-51. PubMed.
  3. Frischknecht R, Gundelfinger ED. The brain's extracellular matrix and its role in synaptic plasticity. Adv Exp Med Biol. 2012;970:153-71. PubMed.
  4. Lensjø KK, Lepperød ME, Dick G, Hafting T, Fyhn M. Removal of Perineuronal Nets Unlocks Juvenile Plasticity Through Network Mechanisms of Decreased Inhibition and Increased Gamma Activity. J Neurosci. 2017 Feb 1;37(5):1269-1283. Epub 2016 Dec 30 PubMed.
  5. Matuszko G, Curreli S, Kaushik R, Becker A, Dityatev A. Extracellular matrix alterations in the ketamine model of schizophrenia. Neuroscience. 2017 May 14;350:13-22. Epub 2017 Mar 18 PubMed.
  6. Kaushik R, Lipachev N, Matuszko G, Kochneva A, Dvoeglazova A, Becker A, Paveliev M, Dityatev A. Fine structure analysis of perineuronal nets in the ketamine model of schizophrenia. Eur J Neurosci. 2021 Jun;53(12):3988-4004. Epub 2020 Jun 25 PubMed.
  7. Carboni E, Carta AR, Carboni E, Novelli A. Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?. Front Neurosci. 2021;15:657714. Epub 2021 Apr 30 PubMed.
  8. Liriano F, Hatten C, Schwartz TL. Ketamine as treatment for post-traumatic stress disorder: a review. Drugs Context. 2019;8:212305. Epub 2019 Apr 8 PubMed.
  9. Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, Viscusi ER, Narouze S, Davis FN, Ritchie EC, Lubenow TR, Hooten WM. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018 Jul;43(5):521-546. PubMed.
  10. Krystal JH, Abdallah CG, Averill LA, Kelmendi B, Harpaz-Rotem I, Sanacora G, Southwick SM, Duman RS. Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic. Curr Psychiatry Rep. 2017 Aug 26;19(10):74. PubMed.
  11. Pinault D. N-methyl d-aspartate receptor antagonists ketamine and MK-801 induce wake-related aberrant gamma oscillations in the rat neocortex. Biol Psychiatry. 2008 Apr 15;63(8):730-5. Epub 2007 Nov 26 PubMed.
  12. Ahnaou A, Huysmans H, Biermans R, Manyakov NV, Drinkenburg WH. Ketamine: differential neurophysiological dynamics in functional networks in the rat brain. Transl Psychiatry. 2017 Sep 19;7(9):e1237. PubMed.
  13. Castro-Zaballa S, Cavelli ML, Gonzalez J, Nardi AE, Machado S, Scorza C, Torterolo P. EEG 40 Hz Coherence Decreases in REM Sleep and Ketamine Model of Psychosis. Front Psychiatry. 2018;9:766. Epub 2019 Jan 17 PubMed.
  14. Sipe GO, Lowery RL, Tremblay MÈ, Kelly EA, Lamantia CE, Majewska AK. Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat Commun. 2016 Mar 7;7:10905. PubMed.
  15. 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.
  16. 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.
  17. Cserép C, Pósfai B, Lénárt N, Fekete R, László ZI, Lele Z, Orsolits B, Molnár G, Heindl S, Schwarcz AD, Ujvári K, Környei Z, Tóth K, Szabadits E, Sperlágh B, Baranyi M, Csiba L, Hortobágyi T, Maglóczky Z, Martinecz B, Szabó G, Erdélyi F, Szipőcs R, Tamkun MM, Gesierich B, Duering M, Katona I, Liesz A, Tamás G, Dénes Á. Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science. 2020 Jan 31;367(6477):528-537. Epub 2019 Dec 12 PubMed.
  18. Maynard TM, Sikich L, Lieberman JA, LaMantia AS. Neural development, cell-cell signaling, and the "two-hit" hypothesis of schizophrenia. Schizophr Bull. 2001;27(3):457-76. PubMed.
  19. Giovanoli S, Engler H, Engler A, Richetto J, Feldon J, Riva MA, Schedlowski M, Meyer U. Preventive effects of minocycline in a neurodevelopmental two-hit model with relevance to schizophrenia. Transl Psychiatry. 2016 Apr 5;6:e772. PubMed.
  20. Mottahedin A, Ardalan M, Chumak T, Riebe I, Ek J, Mallard C. Effect of Neuroinflammation on Synaptic Organization and Function in the Developing Brain: Implications for Neurodevelopmental and Neurodegenerative Disorders. Front Cell Neurosci. 2017;11:190. Epub 2017 Jul 11 PubMed.
  21. Gan AM, Butoi ED, Manea A, Simion V, Stan D, Parvulescu MM, Calin M, Manduteanu I, Simionescu M. Inflammatory effects of resistin on human smooth muscle cells: up-regulation of fractalkine and its receptor, CX3CR1 expression by TLR4 and Gi-protein pathways. Cell Tissue Res. 2013 Jan;351(1):161-74. Epub 2012 Oct 20 PubMed.
  22. Papageorgiou IE, Lewen A, Galow LV, Cesetti T, Scheffel J, Regen T, Hanisch UK, Kann O. TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ. Proc Natl Acad Sci U S A. 2016 Jan 5;113(1):212-7. Epub 2015 Dec 22 PubMed.
  23. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011 Sep 9;333(6048):1456-8. PubMed.
  24. Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, Vyssotski AL, Bifone A, Gozzi A, Ragozzino D, Gross CT. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci. 2014 Mar;17(3):400-6. Epub 2014 Feb 2 PubMed.
  25. Enomoto S, Kato TA. [Stress Mediated Microglial Hyper-Activation and Psychiatric Diseases]. Brain Nerve. 2021 Jul;73(7):795-802. PubMed.
  26. Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci U S A. 2021 Apr 27;118(17) PubMed.
  27. Shao LX, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, Kwan AC. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron. 2021 Jun 25; PubMed.
  28. Krediet E, Bostoen T, Breeksema J, van Schagen A, Passie T, Vermetten E. Reviewing the Potential of Psychedelics for the Treatment of PTSD. Int J Neuropsychopharmacol. 2020 Jun 24;23(6):385-400. PubMed.

Further Reading

Primary Papers

  1. 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.
  2. Venturino A, Schulz R, De Jesús-Cortés H, Maes ME, Nagy B, Reilly-Andújar F, Colombo G, Cubero RJ, Schoot Uiterkamp FE, Bear MF, Siegert S. Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain. Cell Rep. 2021 Jul 6;36(1):109313. PubMed.
  3. Cao P, Chen C, Liu A, Shan Q, Zhu X, Jia C, Peng X, Zhang M, Farzinpour Z, Zhou W, Wang H, Zhou JN, Song X, Wang L, Tao W, Zheng C, Zhang Y, Ding YQ, Jin Y, Xu L, Zhang Z. Early-life inflammation promotes depressive symptoms in adolescence via microglial engulfment of dendritic spines. Neuron. 2021 Jun 26; PubMed.

Annotate

To make an annotation you must Login or Register.