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Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain.

Chen Z, Jalabi W, Hu W, Park HJ, Gale JT, Kidd GJ, Bernatowicz R, Gossman ZC, Chen JT, Dutta R, Trapp BD - Nat Commun (2014)

Bottom Line: Electrophysiological recordings further establish that the reduction in inhibitory GABAergic synapses increased synchronized firing of cortical neurons in γ-frequency band.Increased neuronal activity results in the calcium-mediated activation of CaM kinase IV, phosphorylation of CREB, increased expression of antiapoptotic and neurotrophic molecules and reduced apoptosis of cortical neurons following injury.These results indicate that activated microglia can protect the adult brain by migrating to inhibitory synapses and displacing them from cortical neurons.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [2].

ABSTRACT
Microglia actively survey the brain microenvironment and play essential roles in sculpting synaptic connections during brain development. While microglial functions in the adult brain are less clear, activated microglia can closely appose neuronal cell bodies and displace axosomatic presynaptic terminals. Microglia-mediated stripping of presynaptic terminals is considered neuroprotective, but the cellular and molecular mechanisms are poorly defined. Using 3D electron microscopy, we demonstrate that activated microglia displace inhibitory presynaptic terminals from cortical neurons in adult mice. Electrophysiological recordings further establish that the reduction in inhibitory GABAergic synapses increased synchronized firing of cortical neurons in γ-frequency band. Increased neuronal activity results in the calcium-mediated activation of CaM kinase IV, phosphorylation of CREB, increased expression of antiapoptotic and neurotrophic molecules and reduced apoptosis of cortical neurons following injury. These results indicate that activated microglia can protect the adult brain by migrating to inhibitory synapses and displacing them from cortical neurons.

No MeSH data available.


Related in: MedlinePlus

Activated microglia target cortical neurons and displace inhibitory synapses from neuronal soma.(a–c) Confocal micrographs show morphological changes of microglia (green) following multiple LPS injections. Arrowheads indicate microglia enwrapping neuronal cell bodies (red). Scale bar, 40 μm. (d) Quantification of the percentage of microglia in contact with neurons. N=3 per group. (e,f) Triple labelling of microglia (blue), neurons (red) and GAD+ inhibitory synapses (green). Scale bar, 10 μm. (g) Quantification of the percentage of neuronal circumference occupied by inhibitory synapses over the indicated time course. N=31 to 55 neurons sampled from six individual mice per group. Error bars represent s.e.m. *P<0.05; **P<0.01 compared with control group using a one-way ANOVA test.
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f1: Activated microglia target cortical neurons and displace inhibitory synapses from neuronal soma.(a–c) Confocal micrographs show morphological changes of microglia (green) following multiple LPS injections. Arrowheads indicate microglia enwrapping neuronal cell bodies (red). Scale bar, 40 μm. (d) Quantification of the percentage of microglia in contact with neurons. N=3 per group. (e,f) Triple labelling of microglia (blue), neurons (red) and GAD+ inhibitory synapses (green). Scale bar, 10 μm. (g) Quantification of the percentage of neuronal circumference occupied by inhibitory synapses over the indicated time course. N=31 to 55 neurons sampled from six individual mice per group. Error bars represent s.e.m. *P<0.05; **P<0.01 compared with control group using a one-way ANOVA test.

Mentions: Intraperitoneal administration of a low dose of LPS (1.0 mg kg−1) for four consecutive days results in global microglial activation in the brain parenchyma and these activated microglia closely appose neuronal perikarya8. Microglial activation is defined by hallmark morphological changes and the upregulation of signature activation markers such as F4/80. Here, we further characterized this activation by quantifying the percentage of total microglia in close apposition with neuronal soma in laminar layers III to V in motor cortices of mice. The temporal changes of this association were followed for 2 weeks after the final LPS or saline injection (Fig. 1; Supplementary Fig. 1). Resting microglia in saline-injected mice had a stellate appearance and no obvious association with neuronal somata (Fig. 1a). Sixteen per cent of these cortical microglia extended processes that closely apposed but never ensheathed neuronal somata or apical dendrites (Fig. 1d). In contrast, 1 day after the final LPS injection (1 day post injection; 1 DPI), 61% of microglia ensheathed neuronal perikarya or extended asymmetrically oriented processes that ensheathed neurons (Fig. 1b,d, arrowheads). These LPS-induced microglial changes were transient, as microglial activation (Supplementary Fig. 1) and their neuronal associations were reduced to 50% at 7 DPI (Fig. 1d), and microglia displayed a resting state morphology at 14 DPI (Fig. 1c,d).


Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain.

Chen Z, Jalabi W, Hu W, Park HJ, Gale JT, Kidd GJ, Bernatowicz R, Gossman ZC, Chen JT, Dutta R, Trapp BD - Nat Commun (2014)

Activated microglia target cortical neurons and displace inhibitory synapses from neuronal soma.(a–c) Confocal micrographs show morphological changes of microglia (green) following multiple LPS injections. Arrowheads indicate microglia enwrapping neuronal cell bodies (red). Scale bar, 40 μm. (d) Quantification of the percentage of microglia in contact with neurons. N=3 per group. (e,f) Triple labelling of microglia (blue), neurons (red) and GAD+ inhibitory synapses (green). Scale bar, 10 μm. (g) Quantification of the percentage of neuronal circumference occupied by inhibitory synapses over the indicated time course. N=31 to 55 neurons sampled from six individual mice per group. Error bars represent s.e.m. *P<0.05; **P<0.01 compared with control group using a one-way ANOVA test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109015&req=5

f1: Activated microglia target cortical neurons and displace inhibitory synapses from neuronal soma.(a–c) Confocal micrographs show morphological changes of microglia (green) following multiple LPS injections. Arrowheads indicate microglia enwrapping neuronal cell bodies (red). Scale bar, 40 μm. (d) Quantification of the percentage of microglia in contact with neurons. N=3 per group. (e,f) Triple labelling of microglia (blue), neurons (red) and GAD+ inhibitory synapses (green). Scale bar, 10 μm. (g) Quantification of the percentage of neuronal circumference occupied by inhibitory synapses over the indicated time course. N=31 to 55 neurons sampled from six individual mice per group. Error bars represent s.e.m. *P<0.05; **P<0.01 compared with control group using a one-way ANOVA test.
Mentions: Intraperitoneal administration of a low dose of LPS (1.0 mg kg−1) for four consecutive days results in global microglial activation in the brain parenchyma and these activated microglia closely appose neuronal perikarya8. Microglial activation is defined by hallmark morphological changes and the upregulation of signature activation markers such as F4/80. Here, we further characterized this activation by quantifying the percentage of total microglia in close apposition with neuronal soma in laminar layers III to V in motor cortices of mice. The temporal changes of this association were followed for 2 weeks after the final LPS or saline injection (Fig. 1; Supplementary Fig. 1). Resting microglia in saline-injected mice had a stellate appearance and no obvious association with neuronal somata (Fig. 1a). Sixteen per cent of these cortical microglia extended processes that closely apposed but never ensheathed neuronal somata or apical dendrites (Fig. 1d). In contrast, 1 day after the final LPS injection (1 day post injection; 1 DPI), 61% of microglia ensheathed neuronal perikarya or extended asymmetrically oriented processes that ensheathed neurons (Fig. 1b,d, arrowheads). These LPS-induced microglial changes were transient, as microglial activation (Supplementary Fig. 1) and their neuronal associations were reduced to 50% at 7 DPI (Fig. 1d), and microglia displayed a resting state morphology at 14 DPI (Fig. 1c,d).

Bottom Line: Electrophysiological recordings further establish that the reduction in inhibitory GABAergic synapses increased synchronized firing of cortical neurons in γ-frequency band.Increased neuronal activity results in the calcium-mediated activation of CaM kinase IV, phosphorylation of CREB, increased expression of antiapoptotic and neurotrophic molecules and reduced apoptosis of cortical neurons following injury.These results indicate that activated microglia can protect the adult brain by migrating to inhibitory synapses and displacing them from cortical neurons.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [2].

ABSTRACT
Microglia actively survey the brain microenvironment and play essential roles in sculpting synaptic connections during brain development. While microglial functions in the adult brain are less clear, activated microglia can closely appose neuronal cell bodies and displace axosomatic presynaptic terminals. Microglia-mediated stripping of presynaptic terminals is considered neuroprotective, but the cellular and molecular mechanisms are poorly defined. Using 3D electron microscopy, we demonstrate that activated microglia displace inhibitory presynaptic terminals from cortical neurons in adult mice. Electrophysiological recordings further establish that the reduction in inhibitory GABAergic synapses increased synchronized firing of cortical neurons in γ-frequency band. Increased neuronal activity results in the calcium-mediated activation of CaM kinase IV, phosphorylation of CREB, increased expression of antiapoptotic and neurotrophic molecules and reduced apoptosis of cortical neurons following injury. These results indicate that activated microglia can protect the adult brain by migrating to inhibitory synapses and displacing them from cortical neurons.

No MeSH data available.


Related in: MedlinePlus