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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 GABAergic synaptic transmission at cortical pyramidal neurons dominantly.Spontaneous IPSCs (sIPSC) were recorded by whole-cell voltage-clamp without stimulating presynaptic axons under the conditions of control and then extracellular acidification versus of control and intracellular acidification. A) shows the recorded sIPSCs under the control (top trace), intracellular acidification (middle trace) and extracellular acidification (bottom trace). B) illustrates the differences of sIPSC amplitudes between control and intracellular acidosis (∆IPSC amplitudes, red bar) as well as the ∆IPSC amplitudes between control and extracellular acidosis (blue bar; two asterisks, p<0.01, n = 15; one-way ANOVA). C) illustrates the differences of inter-sIPSC intervals between control and intracellular acidosis (∆inter-IPSC interval, red bar) as well as ∆inter-IPSC intervals between control and extracellular acidosis (blue bar; two asterisks, p<0.01, n = 15; one-way ANOVA).
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pone.0140324.g003: Extracellular acidosis impairs GABAergic synaptic transmission at cortical pyramidal neurons dominantly.Spontaneous IPSCs (sIPSC) were recorded by whole-cell voltage-clamp without stimulating presynaptic axons under the conditions of control and then extracellular acidification versus of control and intracellular acidification. A) shows the recorded sIPSCs under the control (top trace), intracellular acidification (middle trace) and extracellular acidification (bottom trace). B) illustrates the differences of sIPSC amplitudes between control and intracellular acidosis (∆IPSC amplitudes, red bar) as well as the ∆IPSC amplitudes between control and extracellular acidosis (blue bar; two asterisks, p<0.01, n = 15; one-way ANOVA). C) illustrates the differences of inter-sIPSC intervals between control and intracellular acidosis (∆inter-IPSC interval, red bar) as well as ∆inter-IPSC intervals between control and extracellular acidosis (blue bar; two asterisks, p<0.01, n = 15; one-way ANOVA).

Mentions: The influences of intracellular and extracellular acidosis on the synaptic outputs of GABAergic neurons are shown in Fig 3. Intracellular acidosis appears to reduce GABAergic synaptic transmission (Fig 3A). The difference of sIPSC amplitudes (∆sIPSC amplitudes) between control and intracellular acidosis is 0.38±0.03 pA. ∆sIPSC amplitude between control and extracellular acidosis is 0.77±0.08 pA. The net decreases in sIPSC amplitudes by extracellular acidosis versus intracellular acidosis are statistical difference (p<0.01, n = 15; one-way ANOVA in Fig 3B). Furthermore, the difference of inter-sIPSC intervals (i.e., ∆inter-sIPSC intervals) before and after intracellular acidosis is 41.5±1.5 ms. ∆inter-sIPSC interval before and after extracellular acidosis is 63.7±2.1 ms. The net decreases in sIPSC frequencies by extracellular acidosis vs. intracellular acidosis are statistical difference (p<0.01, n = 15; one-way ANOVA in Fig 3C). These results indicate that both intracellular acidosis and extracellular acidosis deteriorate GABAergic synaptic functions, but extracellular acidosis more severely impairs the synaptic outputs from GABAergic neurons.


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 GABAergic synaptic transmission at cortical pyramidal neurons dominantly.Spontaneous IPSCs (sIPSC) were recorded by whole-cell voltage-clamp without stimulating presynaptic axons under the conditions of control and then extracellular acidification versus of control and intracellular acidification. A) shows the recorded sIPSCs under the control (top trace), intracellular acidification (middle trace) and extracellular acidification (bottom trace). B) illustrates the differences of sIPSC amplitudes between control and intracellular acidosis (∆IPSC amplitudes, red bar) as well as the ∆IPSC amplitudes between control and extracellular acidosis (blue bar; two asterisks, p<0.01, n = 15; one-way ANOVA). C) illustrates the differences of inter-sIPSC intervals between control and intracellular acidosis (∆inter-IPSC interval, red bar) as well as ∆inter-IPSC intervals between control and extracellular acidosis (blue bar; two asterisks, 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.g003: Extracellular acidosis impairs GABAergic synaptic transmission at cortical pyramidal neurons dominantly.Spontaneous IPSCs (sIPSC) were recorded by whole-cell voltage-clamp without stimulating presynaptic axons under the conditions of control and then extracellular acidification versus of control and intracellular acidification. A) shows the recorded sIPSCs under the control (top trace), intracellular acidification (middle trace) and extracellular acidification (bottom trace). B) illustrates the differences of sIPSC amplitudes between control and intracellular acidosis (∆IPSC amplitudes, red bar) as well as the ∆IPSC amplitudes between control and extracellular acidosis (blue bar; two asterisks, p<0.01, n = 15; one-way ANOVA). C) illustrates the differences of inter-sIPSC intervals between control and intracellular acidosis (∆inter-IPSC interval, red bar) as well as ∆inter-IPSC intervals between control and extracellular acidosis (blue bar; two asterisks, p<0.01, n = 15; one-way ANOVA).
Mentions: The influences of intracellular and extracellular acidosis on the synaptic outputs of GABAergic neurons are shown in Fig 3. Intracellular acidosis appears to reduce GABAergic synaptic transmission (Fig 3A). The difference of sIPSC amplitudes (∆sIPSC amplitudes) between control and intracellular acidosis is 0.38±0.03 pA. ∆sIPSC amplitude between control and extracellular acidosis is 0.77±0.08 pA. The net decreases in sIPSC amplitudes by extracellular acidosis versus intracellular acidosis are statistical difference (p<0.01, n = 15; one-way ANOVA in Fig 3B). Furthermore, the difference of inter-sIPSC intervals (i.e., ∆inter-sIPSC intervals) before and after intracellular acidosis is 41.5±1.5 ms. ∆inter-sIPSC interval before and after extracellular acidosis is 63.7±2.1 ms. The net decreases in sIPSC frequencies by extracellular acidosis vs. intracellular acidosis are statistical difference (p<0.01, n = 15; one-way ANOVA in Fig 3C). These results indicate that both intracellular acidosis and extracellular acidosis deteriorate GABAergic synaptic functions, but extracellular acidosis more severely impairs the synaptic outputs from GABAergic neurons.

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