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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 GABAergic synaptic outputs to cortical pyramidal neurons induced by extracellular acidosis.sIPSCs were recorded by whole-cell voltage-clamp under the conditions of sequential manipulations, i.e., control, extracellular acidosis and extracellular acidosis plus 10 μM CNQX and 40 μM D-AP5. A) shows the recorded sIPSCs under the control (top trace), extracellular acidification (middle trace) and extracellular acidification plus glutamate receptor blockers (bottom trace). B) shows the averaged values of sIPSC amplitudes under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar; two asterisks, p<0.01; ##, p<0.01; n = 15; one-way ANOVA). C) shows the averaged values of inter-sIPSC intervals under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar; two asterisks, p<0.01; ##, p<0.01; n = 15; one-way ANOVA).
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pone.0140324.g007: The inhibition of glutamate receptors partially reverses the impairment of GABAergic synaptic outputs to cortical pyramidal neurons induced by extracellular acidosis.sIPSCs were recorded by whole-cell voltage-clamp under the conditions of sequential manipulations, i.e., control, extracellular acidosis and extracellular acidosis plus 10 μM CNQX and 40 μM D-AP5. A) shows the recorded sIPSCs under the control (top trace), extracellular acidification (middle trace) and extracellular acidification plus glutamate receptor blockers (bottom trace). B) shows the averaged values of sIPSC amplitudes under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar; two asterisks, p<0.01; ##, p<0.01; n = 15; one-way ANOVA). C) shows the averaged values of inter-sIPSC intervals under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar; two asterisks, p<0.01; ##, p<0.01; n = 15; one-way ANOVA).

Mentions: The influence of inhibiting glutamate receptors on the synaptic outputs from GABAergic neurons is showed in Fig 7. The dysfunction of GABAergic synapses induced by extracellular acidosis appears to be partially reversed by 10 µM CNQX/40 µM D-AP5 (Fig 7A). sIPSC amplitudes are 16.52±0.17 pA under the control, 15.76±0.15 pA during extracellular acidosis and 16.1±0.16 pA during extracellular acidosis in the presence of CNQX and D-AP5 (Fig 7B; p<0.01, n = 12, one-way ANOVA). Inter-sIPSC intervals are 151.5±1.1 ms under control, 87.6±1.5 ms in extracellular acidosis and 106.1±2.1 ms during extracellular acidosis plus CNQX/D-AP5 (p<0.01, n = 12, one-way ANOVA in Fig 7C). This partial reverse of acidosis-induced GABAergic synapse injury by blocking glutamate receptors indicates 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 GABAergic synaptic outputs to cortical pyramidal neurons induced by extracellular acidosis.sIPSCs were recorded by whole-cell voltage-clamp under the conditions of sequential manipulations, i.e., control, extracellular acidosis and extracellular acidosis plus 10 μM CNQX and 40 μM D-AP5. A) shows the recorded sIPSCs under the control (top trace), extracellular acidification (middle trace) and extracellular acidification plus glutamate receptor blockers (bottom trace). B) shows the averaged values of sIPSC amplitudes under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar; two asterisks, p<0.01; ##, p<0.01; n = 15; one-way ANOVA). C) shows the averaged values of inter-sIPSC intervals under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar; two asterisks, p<0.01; ##, p<0.01; n = 15; one-way ANOVA).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608795&req=5

pone.0140324.g007: The inhibition of glutamate receptors partially reverses the impairment of GABAergic synaptic outputs to cortical pyramidal neurons induced by extracellular acidosis.sIPSCs were recorded by whole-cell voltage-clamp under the conditions of sequential manipulations, i.e., control, extracellular acidosis and extracellular acidosis plus 10 μM CNQX and 40 μM D-AP5. A) shows the recorded sIPSCs under the control (top trace), extracellular acidification (middle trace) and extracellular acidification plus glutamate receptor blockers (bottom trace). B) shows the averaged values of sIPSC amplitudes under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar; two asterisks, p<0.01; ##, p<0.01; n = 15; one-way ANOVA). C) shows the averaged values of inter-sIPSC intervals under the conditions of control (red bar), extracellular acidosis (blue bar) and extracellular acidosis plus glutamate receptor blockers (green bar; two asterisks, p<0.01; ##, p<0.01; n = 15; one-way ANOVA).
Mentions: The influence of inhibiting glutamate receptors on the synaptic outputs from GABAergic neurons is showed in Fig 7. The dysfunction of GABAergic synapses induced by extracellular acidosis appears to be partially reversed by 10 µM CNQX/40 µM D-AP5 (Fig 7A). sIPSC amplitudes are 16.52±0.17 pA under the control, 15.76±0.15 pA during extracellular acidosis and 16.1±0.16 pA during extracellular acidosis in the presence of CNQX and D-AP5 (Fig 7B; p<0.01, n = 12, one-way ANOVA). Inter-sIPSC intervals are 151.5±1.1 ms under control, 87.6±1.5 ms in extracellular acidosis and 106.1±2.1 ms during extracellular acidosis plus CNQX/D-AP5 (p<0.01, n = 12, one-way ANOVA in Fig 7C). This partial reverse of acidosis-induced GABAergic synapse injury by blocking glutamate receptors indicates 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