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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 and intracellular acidosis prolongs the refractory periods of action potentials at the cortical GABAergic neurons.Refractory periods were measured by injecting paired-depolarization pulses and recorded under whole-cell current-clamp. A) shows the measurements of refractory periods under the control (red trace) and subsequent intracellular acidification (blue), respectively. B) shows the averaged values of spike refractory periods under the conditions of control (pH 7.35, red bar) and intracellular acidification (pH 6.75; blue). Two asterisks show p<0.01 (n = 15, paired t-test). C) shows the measurement refractory periods under the control (red trace) and extracellular acidification (dark blue), respectively. D) shows the values of refractory periods under the conditions of control (pH 7.35, red bar) and extracellular acidification (pH 6.75; dark-blue). Two asterisks show p<0.01 (n = 15, paired t-test).
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pone.0140324.g002: Extracellular and intracellular acidosis prolongs the refractory periods of action potentials at the cortical GABAergic neurons.Refractory periods were measured by injecting paired-depolarization pulses and recorded under whole-cell current-clamp. A) shows the measurements of refractory periods under the control (red trace) and subsequent intracellular acidification (blue), respectively. B) shows the averaged values of spike refractory periods under the conditions of control (pH 7.35, red bar) and intracellular acidification (pH 6.75; blue). Two asterisks show p<0.01 (n = 15, paired t-test). C) shows the measurement refractory periods under the control (red trace) and extracellular acidification (dark blue), respectively. D) shows the values of refractory periods under the conditions of control (pH 7.35, red bar) and extracellular acidification (pH 6.75; dark-blue). Two asterisks show p<0.01 (n = 15, paired t-test).

Mentions: The influences of intracellular and extracellular acidosis on the spiking ability and active intrinsic properties of cortical GABAergic neurons are shown in Fig 1. Intracellular acidosis appears to reduce the spiking ability of GABAergic neurons (Fig 1A). Spike frequencies at the maximal level of input-outputs are 127.5±2.99 Hz before acidosis and 103.3±1.97 Hz after acidosis (Fig 1B; p<0.01, n = 15; paired t-test). Extracellular acidosis appears also to attenuate the spiking ability of GABAergic neurons (Fig 1C). Spike frequencies at the maximal level of input-output are 127.5±2.99 Hz before acidosis and 100.4±2.0 Hz after acidosis (Fig 1D; p<0.01, n = 15; paired t-test). Thus, both intracellular and extracellular acidifications impair GABAergic neurons in their spiking ability. In terms of active intrinsic property, both intracellular and extracellular acidifications elevate threshold potentials to fire spikes (dash lines in Fig 1A and 1C) and prolong spike refractory periods (Fig 2A and 2C). The refractory periods are 3.96±0.06 ms before intracellular acidosis and 4.45±0.06 ms after acidosis (Fig 2B; p<0.01, n = 15; paired t-test). The refractory periods are 3.96±0.06 ms before extracellular acidosis and 4.53±0.07 ms after acidosis (Fig 2D; p<0.01, n = 15; paired t-test). The results indicate that both intracellular acidosis and extracellular acidosis impair GABAergic neurons in their active intrinsic properties to lower spiking capability.


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 and intracellular acidosis prolongs the refractory periods of action potentials at the cortical GABAergic neurons.Refractory periods were measured by injecting paired-depolarization pulses and recorded under whole-cell current-clamp. A) shows the measurements of refractory periods under the control (red trace) and subsequent intracellular acidification (blue), respectively. B) shows the averaged values of spike refractory periods under the conditions of control (pH 7.35, red bar) and intracellular acidification (pH 6.75; blue). Two asterisks show p<0.01 (n = 15, paired t-test). C) shows the measurement refractory periods under the control (red trace) and extracellular acidification (dark blue), respectively. D) shows the values of refractory periods under the conditions of control (pH 7.35, red bar) and extracellular acidification (pH 6.75; dark-blue). Two asterisks show p<0.01 (n = 15, paired t-test).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140324.g002: Extracellular and intracellular acidosis prolongs the refractory periods of action potentials at the cortical GABAergic neurons.Refractory periods were measured by injecting paired-depolarization pulses and recorded under whole-cell current-clamp. A) shows the measurements of refractory periods under the control (red trace) and subsequent intracellular acidification (blue), respectively. B) shows the averaged values of spike refractory periods under the conditions of control (pH 7.35, red bar) and intracellular acidification (pH 6.75; blue). Two asterisks show p<0.01 (n = 15, paired t-test). C) shows the measurement refractory periods under the control (red trace) and extracellular acidification (dark blue), respectively. D) shows the values of refractory periods under the conditions of control (pH 7.35, red bar) and extracellular acidification (pH 6.75; dark-blue). Two asterisks show p<0.01 (n = 15, paired t-test).
Mentions: The influences of intracellular and extracellular acidosis on the spiking ability and active intrinsic properties of cortical GABAergic neurons are shown in Fig 1. Intracellular acidosis appears to reduce the spiking ability of GABAergic neurons (Fig 1A). Spike frequencies at the maximal level of input-outputs are 127.5±2.99 Hz before acidosis and 103.3±1.97 Hz after acidosis (Fig 1B; p<0.01, n = 15; paired t-test). Extracellular acidosis appears also to attenuate the spiking ability of GABAergic neurons (Fig 1C). Spike frequencies at the maximal level of input-output are 127.5±2.99 Hz before acidosis and 100.4±2.0 Hz after acidosis (Fig 1D; p<0.01, n = 15; paired t-test). Thus, both intracellular and extracellular acidifications impair GABAergic neurons in their spiking ability. In terms of active intrinsic property, both intracellular and extracellular acidifications elevate threshold potentials to fire spikes (dash lines in Fig 1A and 1C) and prolong spike refractory periods (Fig 2A and 2C). The refractory periods are 3.96±0.06 ms before intracellular acidosis and 4.45±0.06 ms after acidosis (Fig 2B; p<0.01, n = 15; paired t-test). The refractory periods are 3.96±0.06 ms before extracellular acidosis and 4.53±0.07 ms after acidosis (Fig 2D; p<0.01, n = 15; paired t-test). The results indicate that both intracellular acidosis and extracellular acidosis impair GABAergic neurons in their active intrinsic properties to lower spiking capability.

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