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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 impairs the glutamate transporter current (GTC) on the cortical astrocytes.The GTCs were recorded on cortical astrocytes and evoked by stimulating presynaptic axons. A) shows the superimposed waveforms of GTCs before (red trace) and after extracellular acidification (blue trace). B) shows the averaged values of GTCs before (red bar) and after extracellular acidification (blue bar; two asterisks, p<0.01, n = 16; paired t-test).
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pone.0140324.g005: Extracellular acidosis impairs the glutamate transporter current (GTC) on the cortical astrocytes.The GTCs were recorded on cortical astrocytes and evoked by stimulating presynaptic axons. A) shows the superimposed waveforms of GTCs before (red trace) and after extracellular acidification (blue trace). B) shows the averaged values of GTCs before (red bar) and after extracellular acidification (blue bar; two asterisks, p<0.01, n = 16; paired t-test).

Mentions: Glutamate transporter currents (GTC) were recorded at the astrocytes in cortical slices to assess astrocytic function since the glutamate uptake from synaptic clefts was one of major astrocytic functions [33–35]. Astrocytic GTCs were recorded by whole-cell voltage-clamp when the presynaptic axons were stimulated. Extracellular acidosis appears to reduce astrocytic GTCs (Fig 5A). The averaged GTC amplitudes are 68.48±3.28 pA under the control and 43.2±4.38 pA after acidosis (asterisks, p<0.01, n = 16; paired t-test in Fig 5B). It is noteworthy that the recorded GTCs are blocked by 10 μM TBOA (glutamate transporter antagonist; [36,37], i.e., the activity of glutamate transporters is recorded (S1 Fig). This result indicates that extracellular acidosis impairs the function of astrocytic glutamate transporter and the uptake of glutamates, such that the accumulated glutamates in synaptic clefts make GABAergic neurons injured.


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 impairs the glutamate transporter current (GTC) on the cortical astrocytes.The GTCs were recorded on cortical astrocytes and evoked by stimulating presynaptic axons. A) shows the superimposed waveforms of GTCs before (red trace) and after extracellular acidification (blue trace). B) shows the averaged values of GTCs before (red bar) and after extracellular acidification (blue bar; two asterisks, p<0.01, n = 16; paired t-test).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140324.g005: Extracellular acidosis impairs the glutamate transporter current (GTC) on the cortical astrocytes.The GTCs were recorded on cortical astrocytes and evoked by stimulating presynaptic axons. A) shows the superimposed waveforms of GTCs before (red trace) and after extracellular acidification (blue trace). B) shows the averaged values of GTCs before (red bar) and after extracellular acidification (blue bar; two asterisks, p<0.01, n = 16; paired t-test).
Mentions: Glutamate transporter currents (GTC) were recorded at the astrocytes in cortical slices to assess astrocytic function since the glutamate uptake from synaptic clefts was one of major astrocytic functions [33–35]. Astrocytic GTCs were recorded by whole-cell voltage-clamp when the presynaptic axons were stimulated. Extracellular acidosis appears to reduce astrocytic GTCs (Fig 5A). The averaged GTC amplitudes are 68.48±3.28 pA under the control and 43.2±4.38 pA after acidosis (asterisks, p<0.01, n = 16; paired t-test in Fig 5B). It is noteworthy that the recorded GTCs are blocked by 10 μM TBOA (glutamate transporter antagonist; [36,37], i.e., the activity of glutamate transporters is recorded (S1 Fig). This result indicates that extracellular acidosis impairs the function of astrocytic glutamate transporter and the uptake of glutamates, such that the accumulated glutamates in synaptic clefts make GABAergic neurons injured.

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