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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

Reduced GABAergic neurotransmission results in increased neuronal firing.(a) Representative raw traces of local field potentials recorded from motor cortex of control (top) or LPS-injected animals (bottom) before (red), during (green) or after (blue) the 4-day injection regimen. (b) Power spectra density between 10 and 50-Hz frequencies of individual animals. Arrow indicates an increase in power spectra in the 20–40 Hz band in LPS-treated animals. Solid lines indicate mean power and shades represent s.d.; colour scheme is the same as in a. (c) Local field potentials were band filtered to show the power of the 20–40 Hz frequency. (d) Power spectral densities of low γ-band (20–40 Hz) field potentials were calculated for control (blue, n=3) and LPS-injected (red, n=5) animals. Data are represented as mean±s.e.m before (‘pre-’), during (‘0’ denotes first day of LPS injection) and after (‘early-’ or ‘late-post’) LPS injections. **P<0.01; two-way ANOVA. (e) The recordings were grouped into four stages relative to the LPS injections. The mean+s.e.m of each stage are shown. **P<0.01; NS, not significant; two-way ANOVA.
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f3: Reduced GABAergic neurotransmission results in increased neuronal firing.(a) Representative raw traces of local field potentials recorded from motor cortex of control (top) or LPS-injected animals (bottom) before (red), during (green) or after (blue) the 4-day injection regimen. (b) Power spectra density between 10 and 50-Hz frequencies of individual animals. Arrow indicates an increase in power spectra in the 20–40 Hz band in LPS-treated animals. Solid lines indicate mean power and shades represent s.d.; colour scheme is the same as in a. (c) Local field potentials were band filtered to show the power of the 20–40 Hz frequency. (d) Power spectral densities of low γ-band (20–40 Hz) field potentials were calculated for control (blue, n=3) and LPS-injected (red, n=5) animals. Data are represented as mean±s.e.m before (‘pre-’), during (‘0’ denotes first day of LPS injection) and after (‘early-’ or ‘late-post’) LPS injections. **P<0.01; two-way ANOVA. (e) The recordings were grouped into four stages relative to the LPS injections. The mean+s.e.m of each stage are shown. **P<0.01; NS, not significant; two-way ANOVA.

Mentions: Local field potentials (Fig. 3a) of a representative animal from the LPS treatment group demonstrates a broadband increase in power across the frequency spectrum centred on the 20–40 Hz frequency band (referred to as γ-band) during and after administration of LPS (arrow, Fig. 3b). In contrast, a representative animal in the control group demonstrates a consistent power spectrum throughout the experiments (Fig. 3b). An increase in power spectral density is an indication of increased firing synchronicity of local neuronal ensembles. In order to make group comparisons between the LPS and control groups, we extracted the power from 20–40 Hz frequency band (Fig. 3c) and examined the aggregate power for each group relative to the treatment phases (Fig. 3d,e).


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)

Reduced GABAergic neurotransmission results in increased neuronal firing.(a) Representative raw traces of local field potentials recorded from motor cortex of control (top) or LPS-injected animals (bottom) before (red), during (green) or after (blue) the 4-day injection regimen. (b) Power spectra density between 10 and 50-Hz frequencies of individual animals. Arrow indicates an increase in power spectra in the 20–40 Hz band in LPS-treated animals. Solid lines indicate mean power and shades represent s.d.; colour scheme is the same as in a. (c) Local field potentials were band filtered to show the power of the 20–40 Hz frequency. (d) Power spectral densities of low γ-band (20–40 Hz) field potentials were calculated for control (blue, n=3) and LPS-injected (red, n=5) animals. Data are represented as mean±s.e.m before (‘pre-’), during (‘0’ denotes first day of LPS injection) and after (‘early-’ or ‘late-post’) LPS injections. **P<0.01; two-way ANOVA. (e) The recordings were grouped into four stages relative to the LPS injections. The mean+s.e.m of each stage are shown. **P<0.01; NS, not significant; two-way ANOVA.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Reduced GABAergic neurotransmission results in increased neuronal firing.(a) Representative raw traces of local field potentials recorded from motor cortex of control (top) or LPS-injected animals (bottom) before (red), during (green) or after (blue) the 4-day injection regimen. (b) Power spectra density between 10 and 50-Hz frequencies of individual animals. Arrow indicates an increase in power spectra in the 20–40 Hz band in LPS-treated animals. Solid lines indicate mean power and shades represent s.d.; colour scheme is the same as in a. (c) Local field potentials were band filtered to show the power of the 20–40 Hz frequency. (d) Power spectral densities of low γ-band (20–40 Hz) field potentials were calculated for control (blue, n=3) and LPS-injected (red, n=5) animals. Data are represented as mean±s.e.m before (‘pre-’), during (‘0’ denotes first day of LPS injection) and after (‘early-’ or ‘late-post’) LPS injections. **P<0.01; two-way ANOVA. (e) The recordings were grouped into four stages relative to the LPS injections. The mean+s.e.m of each stage are shown. **P<0.01; NS, not significant; two-way ANOVA.
Mentions: Local field potentials (Fig. 3a) of a representative animal from the LPS treatment group demonstrates a broadband increase in power across the frequency spectrum centred on the 20–40 Hz frequency band (referred to as γ-band) during and after administration of LPS (arrow, Fig. 3b). In contrast, a representative animal in the control group demonstrates a consistent power spectrum throughout the experiments (Fig. 3b). An increase in power spectral density is an indication of increased firing synchronicity of local neuronal ensembles. In order to make group comparisons between the LPS and control groups, we extracted the power from 20–40 Hz frequency band (Fig. 3c) and examined the aggregate power for each group relative to the treatment phases (Fig. 3d,e).

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