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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

Suppression of microglial activation abolishes neuroprotection.(a) Cortical microglial morphology in mice injected with PBS, LPS or LPS+minocycline (LPS+mino). (b) Neuronal cell body circumferences covered by inhibitory presynaptic terminals were quantified as described in Fig. 1. (c–f) Mice treated with four daily injections of PBS, LPS or LPS+mino underwent cryogenic injury and were killed at 24 h post injury for TUNEL staining (e,f) or at 72 h post injury for lesion volume evaluation (c,d). (c) Tissue injury maps summarizing the average size of the brain lesion following cryo-injury for each group (Control, LPS, LPS+mino). (d) Quantification of lesion volumes. (e) Representative images of TUNEL+ apoptotic cells (red) in the penumbra of the cyro-lesions. Cellular nuclei are counterstained with 4',6-diamidino-2-phenylindole (blue). (f) Quantification of TUNEL+ cells. N=6–8 per group. Data are expressed as mean+s.e.m. *P<0.05, **P<0.01, one-way ANOVA. Scale bar, 20 μm in both a and e.
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f6: Suppression of microglial activation abolishes neuroprotection.(a) Cortical microglial morphology in mice injected with PBS, LPS or LPS+minocycline (LPS+mino). (b) Neuronal cell body circumferences covered by inhibitory presynaptic terminals were quantified as described in Fig. 1. (c–f) Mice treated with four daily injections of PBS, LPS or LPS+mino underwent cryogenic injury and were killed at 24 h post injury for TUNEL staining (e,f) or at 72 h post injury for lesion volume evaluation (c,d). (c) Tissue injury maps summarizing the average size of the brain lesion following cryo-injury for each group (Control, LPS, LPS+mino). (d) Quantification of lesion volumes. (e) Representative images of TUNEL+ apoptotic cells (red) in the penumbra of the cyro-lesions. Cellular nuclei are counterstained with 4',6-diamidino-2-phenylindole (blue). (f) Quantification of TUNEL+ cells. N=6–8 per group. Data are expressed as mean+s.e.m. *P<0.05, **P<0.01, one-way ANOVA. Scale bar, 20 μm in both a and e.

Mentions: Multiple low-dose prophylactic LPS injections induce microglial activation and protect the brain against both cryogenic8 and fluid percussion injuries (Supplementary Fig. 5). To investigate whether microglial activation and synaptic stripping are essential components in this neuroprotection, we used the pharmacological inhibitor minocycline to suppress microglial activation. LPS-induced microglial activation and neuronal association were eliminated by the co-administration of minocycline (Fig. 6a). The neuronal cell surface occupied by inhibitory synapses was not reduced in mice treated with LPS and minocycline (Fig. 6b). Mice that were injected with PBS, LPS or LPS+minocycline were then subjected to cryogenic aseptic brain injury. Seventy-two hours after the injury, mice were killed and the sizes of their brain lesions were analysed (Fig. 6c,d). Mice that were pretreated with LPS had significantly smaller lesion volumes than the PBS control group, indicating that cortical tissue is protected against injury in the presence of activated microglia and synaptic displacement. However, this protection was abolished by the co-administration of LPS and minocycline (Fig. 6d). The decrease in lesion size in the LPS-treated animals relative to PBS control and LPS+minocycline group was associated with a decreased number of apoptotic cells found in the penumbra areas of the lesions 24 h after the injury (Fig. 6e,f), indicating that the reduced lesion size was associated with the induction of the antiapoptotic molecules following microglial synaptic displacement.


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)

Suppression of microglial activation abolishes neuroprotection.(a) Cortical microglial morphology in mice injected with PBS, LPS or LPS+minocycline (LPS+mino). (b) Neuronal cell body circumferences covered by inhibitory presynaptic terminals were quantified as described in Fig. 1. (c–f) Mice treated with four daily injections of PBS, LPS or LPS+mino underwent cryogenic injury and were killed at 24 h post injury for TUNEL staining (e,f) or at 72 h post injury for lesion volume evaluation (c,d). (c) Tissue injury maps summarizing the average size of the brain lesion following cryo-injury for each group (Control, LPS, LPS+mino). (d) Quantification of lesion volumes. (e) Representative images of TUNEL+ apoptotic cells (red) in the penumbra of the cyro-lesions. Cellular nuclei are counterstained with 4',6-diamidino-2-phenylindole (blue). (f) Quantification of TUNEL+ cells. N=6–8 per group. Data are expressed as mean+s.e.m. *P<0.05, **P<0.01, one-way ANOVA. Scale bar, 20 μm in both a and e.
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f6: Suppression of microglial activation abolishes neuroprotection.(a) Cortical microglial morphology in mice injected with PBS, LPS or LPS+minocycline (LPS+mino). (b) Neuronal cell body circumferences covered by inhibitory presynaptic terminals were quantified as described in Fig. 1. (c–f) Mice treated with four daily injections of PBS, LPS or LPS+mino underwent cryogenic injury and were killed at 24 h post injury for TUNEL staining (e,f) or at 72 h post injury for lesion volume evaluation (c,d). (c) Tissue injury maps summarizing the average size of the brain lesion following cryo-injury for each group (Control, LPS, LPS+mino). (d) Quantification of lesion volumes. (e) Representative images of TUNEL+ apoptotic cells (red) in the penumbra of the cyro-lesions. Cellular nuclei are counterstained with 4',6-diamidino-2-phenylindole (blue). (f) Quantification of TUNEL+ cells. N=6–8 per group. Data are expressed as mean+s.e.m. *P<0.05, **P<0.01, one-way ANOVA. Scale bar, 20 μm in both a and e.
Mentions: Multiple low-dose prophylactic LPS injections induce microglial activation and protect the brain against both cryogenic8 and fluid percussion injuries (Supplementary Fig. 5). To investigate whether microglial activation and synaptic stripping are essential components in this neuroprotection, we used the pharmacological inhibitor minocycline to suppress microglial activation. LPS-induced microglial activation and neuronal association were eliminated by the co-administration of minocycline (Fig. 6a). The neuronal cell surface occupied by inhibitory synapses was not reduced in mice treated with LPS and minocycline (Fig. 6b). Mice that were injected with PBS, LPS or LPS+minocycline were then subjected to cryogenic aseptic brain injury. Seventy-two hours after the injury, mice were killed and the sizes of their brain lesions were analysed (Fig. 6c,d). Mice that were pretreated with LPS had significantly smaller lesion volumes than the PBS control group, indicating that cortical tissue is protected against injury in the presence of activated microglia and synaptic displacement. However, this protection was abolished by the co-administration of LPS and minocycline (Fig. 6d). The decrease in lesion size in the LPS-treated animals relative to PBS control and LPS+minocycline group was associated with a decreased number of apoptotic cells found in the penumbra areas of the lesions 24 h after the injury (Fig. 6e,f), indicating that the reduced lesion size was associated with the induction of the antiapoptotic molecules following microglial synaptic displacement.

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