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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

Extracellular acidosis upregulates glutamatergic synaptic transmission at cortical GABAergic neurons dominantly.Spontaneous EPSCs were recorded on GABAergic neurons by whole-cell voltage-clamp without stimulating presynaptic axons. A) shows the recorded sEPSCs under the control (top trace), intracellular acidification (middle trace) and extracellular acidification (bottom trace). B) illustrates the differences of sEPSC amplitudes between intracellular acidosis and control (∆EPSC amplitudes, red bar) as well as the differences between extracellular acidosis and control (∆EPSC amplitudes, blue bar; p<0.01, n = 15; one-way ANOVA). C) shows the differences of inter-sEPSC interval between intracellular acidosis and control (∆inter-IPSC interval, red bar) as well as the differences between extracellular acidosis and control (blue bar; p<0.01, n = 15; one-way ANOVA).
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pone.0140324.g006: Extracellular acidosis upregulates glutamatergic synaptic transmission at cortical GABAergic neurons dominantly.Spontaneous EPSCs were recorded on GABAergic neurons by whole-cell voltage-clamp without stimulating presynaptic axons. A) shows the recorded sEPSCs under the control (top trace), intracellular acidification (middle trace) and extracellular acidification (bottom trace). B) illustrates the differences of sEPSC amplitudes between intracellular acidosis and control (∆EPSC amplitudes, red bar) as well as the differences between extracellular acidosis and control (∆EPSC amplitudes, blue bar; p<0.01, n = 15; one-way ANOVA). C) shows the differences of inter-sEPSC interval between intracellular acidosis and control (∆inter-IPSC interval, red bar) as well as the differences between extracellular acidosis and control (blue bar; p<0.01, n = 15; one-way ANOVA).

Mentions: The effects of extracellular acidosis or intracellular acidosis on the glutamatergic synapses at the GABAergic neurons are showed in Fig 6. Based on the recorded sEPSCs, extracellular or intracellular acidosis appears to increase the activity of excitatory synapses on GABAergic neurons (Fig 6A). The difference of sEPSC amplitudes (∆sEPSC amplitudes) before and after intracellular acidosis is 0.55±0.05 pA. ∆sEPSC amplitude before and after extracellular acidosis is 1.17±0.12 pA. The net changes in sEPSC amplitudes by extracellular acidosis and intracellular acidosis are statistic difference (p<0.01, n = 15, one-way ANOVA; Fig 6B). Furthermore, the difference of inter-sEPSC intervals (∆inter-sEPSC intervals) before and after intracellular acidosis is 93.5±5.1 ms. ∆inter-sEPSC interval before and after extracellular acidosis is 117.9±7 ms. The net increases in sEPSC frequencies by extracellular acidosis and intracellular acidosis are statistic difference (p<0.01, n = 15; one-way ANOVA; Fig 6C). These results indicate that extracellular acidosis dominantly strengthens presynaptic glutamate release and postsynaptic glutamate receptor activity, such that glutamatergic synaptic transmission on the GABAergic neurons is upregulated. This change cannot be corrected during extracellular acidosis as the astrocytic glutamate transporters are dysfunctional to re-uptake the released glutamates (Fig 5).


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)

Extracellular acidosis upregulates glutamatergic synaptic transmission at cortical GABAergic neurons dominantly.Spontaneous EPSCs were recorded on GABAergic neurons by whole-cell voltage-clamp without stimulating presynaptic axons. A) shows the recorded sEPSCs under the control (top trace), intracellular acidification (middle trace) and extracellular acidification (bottom trace). B) illustrates the differences of sEPSC amplitudes between intracellular acidosis and control (∆EPSC amplitudes, red bar) as well as the differences between extracellular acidosis and control (∆EPSC amplitudes, blue bar; p<0.01, n = 15; one-way ANOVA). C) shows the differences of inter-sEPSC interval between intracellular acidosis and control (∆inter-IPSC interval, red bar) as well as the differences between extracellular acidosis and control (blue bar; p<0.01, n = 15; one-way ANOVA).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140324.g006: Extracellular acidosis upregulates glutamatergic synaptic transmission at cortical GABAergic neurons dominantly.Spontaneous EPSCs were recorded on GABAergic neurons by whole-cell voltage-clamp without stimulating presynaptic axons. A) shows the recorded sEPSCs under the control (top trace), intracellular acidification (middle trace) and extracellular acidification (bottom trace). B) illustrates the differences of sEPSC amplitudes between intracellular acidosis and control (∆EPSC amplitudes, red bar) as well as the differences between extracellular acidosis and control (∆EPSC amplitudes, blue bar; p<0.01, n = 15; one-way ANOVA). C) shows the differences of inter-sEPSC interval between intracellular acidosis and control (∆inter-IPSC interval, red bar) as well as the differences between extracellular acidosis and control (blue bar; p<0.01, n = 15; one-way ANOVA).
Mentions: The effects of extracellular acidosis or intracellular acidosis on the glutamatergic synapses at the GABAergic neurons are showed in Fig 6. Based on the recorded sEPSCs, extracellular or intracellular acidosis appears to increase the activity of excitatory synapses on GABAergic neurons (Fig 6A). The difference of sEPSC amplitudes (∆sEPSC amplitudes) before and after intracellular acidosis is 0.55±0.05 pA. ∆sEPSC amplitude before and after extracellular acidosis is 1.17±0.12 pA. The net changes in sEPSC amplitudes by extracellular acidosis and intracellular acidosis are statistic difference (p<0.01, n = 15, one-way ANOVA; Fig 6B). Furthermore, the difference of inter-sEPSC intervals (∆inter-sEPSC intervals) before and after intracellular acidosis is 93.5±5.1 ms. ∆inter-sEPSC interval before and after extracellular acidosis is 117.9±7 ms. The net increases in sEPSC frequencies by extracellular acidosis and intracellular acidosis are statistic difference (p<0.01, n = 15; one-way ANOVA; Fig 6C). These results indicate that extracellular acidosis dominantly strengthens presynaptic glutamate release and postsynaptic glutamate receptor activity, such that glutamatergic synaptic transmission on the GABAergic neurons is upregulated. This change cannot be corrected during extracellular acidosis as the astrocytic glutamate transporters are dysfunctional to re-uptake the released glutamates (Fig 5).

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