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Acidosis-Induced Dysfunction of Cortical GABAergic Neurons through Astrocyte-Related Excitotoxicity.

Huang L, Zhao S, Lu W, Guan S, Zhu Y, Wang JH - PLoS ONE (2015)

Bottom Line: Acidosis impairs cognitions and behaviors presumably by acidification-induced changes in neuronal metabolism.Meanwhile, extracellular acidosis deteriorated glutamate transporter currents on the astrocytes and upregulated excitatory synaptic transmission on the GABAergic neurons.Our studies suggest that acidosis leads to the dysfunction of cortical GABAergic neurons by astrocyte-mediated excitotoxicity, in addition to their metabolic changes as indicated previously.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, Bengbu Medical College, Bengbu Anhui, China 233000.

ABSTRACT

Background: Acidosis impairs cognitions and behaviors presumably by acidification-induced changes in neuronal metabolism. Cortical GABAergic neurons are vulnerable to pathological factors and their injury leads to brain dysfunction. How acidosis induces GABAergic neuron injury remains elusive. As the glia cells and neurons interact each other, we intend to examine the role of the astrocytes in acidosis-induced GABAergic neuron injury.

Results: Experiments were done at GABAergic cells and astrocytes in mouse cortical slices. To identify astrocytic involvement in acidosis-induced impairment, we induced the acidification in single GABAergic neuron by infusing proton intracellularly or in both neurons and astrocytes by using proton extracellularly. Compared the effects of intracellular acidification and extracellular acidification on GABAergic neurons, we found that their active intrinsic properties and synaptic outputs appeared more severely impaired in extracellular acidosis than intracellular acidosis. Meanwhile, extracellular acidosis deteriorated glutamate transporter currents on the astrocytes and upregulated excitatory synaptic transmission on the GABAergic neurons. Moreover, the antagonists of glutamate NMDA-/AMPA-receptors partially reverse extracellular acidosis-induced injury in the GABAergic neurons.

Conclusion: Our studies suggest that acidosis leads to the dysfunction of cortical GABAergic neurons by astrocyte-mediated excitotoxicity, in addition to their metabolic changes as indicated previously.

No MeSH data available.


Related in: MedlinePlus

The inhibition of glutamate receptors partially reverses the impairment of intrinsic properties at cortical GABAergic neurons induced by extracellular acidosis.Sequential spikes, threshold potentials and refractory period at GABAergic neurons were recorded by whole-cell voltage-clamp under the conditions of sequential manipulations, i.e., control, extracellular acidosis and extracellular acidosis plus 40 μM D-AP5 and 10 μM CNQX. A) shows the averaged values of spike frequency under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar). B) shows the averaged values of spike refractory periods under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar). C) shows the averaged values of spike threshold potentials under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar). Two asterisks present p<0.01, such as blue and green bars versus red bar. An asterisk presents p<0.05, such as green bar versus red bar. # presents p<0.05, such as green bar versus blue bar (n = 15; one-way ANOVA).
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pone.0140324.g008: The inhibition of glutamate receptors partially reverses the impairment of intrinsic properties at cortical GABAergic neurons induced by extracellular acidosis.Sequential spikes, threshold potentials and refractory period at GABAergic neurons were recorded by whole-cell voltage-clamp under the conditions of sequential manipulations, i.e., control, extracellular acidosis and extracellular acidosis plus 40 μM D-AP5 and 10 μM CNQX. A) shows the averaged values of spike frequency under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar). B) shows the averaged values of spike refractory periods under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar). C) shows the averaged values of spike threshold potentials under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar). Two asterisks present p<0.01, such as blue and green bars versus red bar. An asterisk presents p<0.05, such as green bar versus red bar. # presents p<0.05, such as green bar versus blue bar (n = 15; one-way ANOVA).

Mentions: We also examined the influences of inhibiting glutamatergic receptors on the intrinsic properties of GABAergic neurons (Fig 8). Extracellular acidosis-induced impairments of their intrinsic properties appear to be partially reversed by 10 μM CNQX and 40 μM D-AP5. Inter-spike intervals are 13.6±0.3 ms under the control, 17.8±0.4 ms in extracellular acidosis and 16.5±0.3 ms during extracellular acidosis in the presence of CNQX and D-AP5 (Fig 8A; p<0.01, n = 12, one-way ANOVA). The refractory periods are 4.7±0.13 ms under the control, 5.5±0.1 ms during extracellular acidosis and 5.1±0.12 ms during extracellular acidosis plus CNQX/D-AP5 (Fig 8B; p<0.01, n = 12, one-way ANOVA). The threshold potentials are 27.1±0.81 mV under control, 36.1±0.9 mV during extracellular acidosis and 33.4±0.89 ms during extracellular acidosis plus CNQX/D-AP5 (Fig 8C; p<0.01, n = 12, one-way ANOVA). These data strengthen an indication that the elevated glutamates during extracellular acidosis impair GABAergic neurons through excitotoxicity.


Acidosis-Induced Dysfunction of Cortical GABAergic Neurons through Astrocyte-Related Excitotoxicity.

Huang L, Zhao S, Lu W, Guan S, Zhu Y, Wang JH - PLoS ONE (2015)

The inhibition of glutamate receptors partially reverses the impairment of intrinsic properties at cortical GABAergic neurons induced by extracellular acidosis.Sequential spikes, threshold potentials and refractory period at GABAergic neurons were recorded by whole-cell voltage-clamp under the conditions of sequential manipulations, i.e., control, extracellular acidosis and extracellular acidosis plus 40 μM D-AP5 and 10 μM CNQX. A) shows the averaged values of spike frequency under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar). B) shows the averaged values of spike refractory periods under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar). C) shows the averaged values of spike threshold potentials under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar). Two asterisks present p<0.01, such as blue and green bars versus red bar. An asterisk presents p<0.05, such as green bar versus red bar. # presents p<0.05, such as green bar versus blue bar (n = 15; one-way ANOVA).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4608795&req=5

pone.0140324.g008: The inhibition of glutamate receptors partially reverses the impairment of intrinsic properties at cortical GABAergic neurons induced by extracellular acidosis.Sequential spikes, threshold potentials and refractory period at GABAergic neurons were recorded by whole-cell voltage-clamp under the conditions of sequential manipulations, i.e., control, extracellular acidosis and extracellular acidosis plus 40 μM D-AP5 and 10 μM CNQX. A) shows the averaged values of spike frequency under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar). B) shows the averaged values of spike refractory periods under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar). C) shows the averaged values of spike threshold potentials under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar). Two asterisks present p<0.01, such as blue and green bars versus red bar. An asterisk presents p<0.05, such as green bar versus red bar. # presents p<0.05, such as green bar versus blue bar (n = 15; one-way ANOVA).
Mentions: We also examined the influences of inhibiting glutamatergic receptors on the intrinsic properties of GABAergic neurons (Fig 8). Extracellular acidosis-induced impairments of their intrinsic properties appear to be partially reversed by 10 μM CNQX and 40 μM D-AP5. Inter-spike intervals are 13.6±0.3 ms under the control, 17.8±0.4 ms in extracellular acidosis and 16.5±0.3 ms during extracellular acidosis in the presence of CNQX and D-AP5 (Fig 8A; p<0.01, n = 12, one-way ANOVA). The refractory periods are 4.7±0.13 ms under the control, 5.5±0.1 ms during extracellular acidosis and 5.1±0.12 ms during extracellular acidosis plus CNQX/D-AP5 (Fig 8B; p<0.01, n = 12, one-way ANOVA). The threshold potentials are 27.1±0.81 mV under control, 36.1±0.9 mV during extracellular acidosis and 33.4±0.89 ms during extracellular acidosis plus CNQX/D-AP5 (Fig 8C; p<0.01, n = 12, one-way ANOVA). These data strengthen an indication that the elevated glutamates during extracellular acidosis impair GABAergic neurons through excitotoxicity.

Bottom Line: Acidosis impairs cognitions and behaviors presumably by acidification-induced changes in neuronal metabolism.Meanwhile, extracellular acidosis deteriorated glutamate transporter currents on the astrocytes and upregulated excitatory synaptic transmission on the GABAergic neurons.Our studies suggest that acidosis leads to the dysfunction of cortical GABAergic neurons by astrocyte-mediated excitotoxicity, in addition to their metabolic changes as indicated previously.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, Bengbu Medical College, Bengbu Anhui, China 233000.

ABSTRACT

Background: Acidosis impairs cognitions and behaviors presumably by acidification-induced changes in neuronal metabolism. Cortical GABAergic neurons are vulnerable to pathological factors and their injury leads to brain dysfunction. How acidosis induces GABAergic neuron injury remains elusive. As the glia cells and neurons interact each other, we intend to examine the role of the astrocytes in acidosis-induced GABAergic neuron injury.

Results: Experiments were done at GABAergic cells and astrocytes in mouse cortical slices. To identify astrocytic involvement in acidosis-induced impairment, we induced the acidification in single GABAergic neuron by infusing proton intracellularly or in both neurons and astrocytes by using proton extracellularly. Compared the effects of intracellular acidification and extracellular acidification on GABAergic neurons, we found that their active intrinsic properties and synaptic outputs appeared more severely impaired in extracellular acidosis than intracellular acidosis. Meanwhile, extracellular acidosis deteriorated glutamate transporter currents on the astrocytes and upregulated excitatory synaptic transmission on the GABAergic neurons. Moreover, the antagonists of glutamate NMDA-/AMPA-receptors partially reverse extracellular acidosis-induced injury in the GABAergic neurons.

Conclusion: Our studies suggest that acidosis leads to the dysfunction of cortical GABAergic neurons by astrocyte-mediated excitotoxicity, in addition to their metabolic changes as indicated previously.

No MeSH data available.


Related in: MedlinePlus