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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 dysfunction of glutamate transporter in the astrocyte leads to the impairment of GABAergic neuron during acidosis.Extracellular acidification impairs the function of astrocytic glutamate transporter (Glu-T), and the subsequent glutamate accumulation deteriorates GABAergic neurons through activating ionotropic glutamate receptors, such as NMDAR and AMPAR.
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pone.0140324.g009: The dysfunction of glutamate transporter in the astrocyte leads to the impairment of GABAergic neuron during acidosis.Extracellular acidification impairs the function of astrocytic glutamate transporter (Glu-T), and the subsequent glutamate accumulation deteriorates GABAergic neurons through activating ionotropic glutamate receptors, such as NMDAR and AMPAR.

Mentions: We examined the involvement of cortical astrocytes in the acidosis-induced injury of GABAergic neurons. Extracellular acidosis impairs the GABAergic neurons in active intrinsic properties and synaptic outputs more severely, in comparison with intracellular acidosis (Figs 1–4). Extracellular acidosis also impairs cortical astrocytes in terms of the re-uptake of glutamates (Fig 5), which is associated with the enhanced glutamatergic synaptic transmission on the GABAergic neurons (Fig 6). These data indicate that astrocytic dysfunction in glutamate uptake and glutamatergic excitation in GABAergic neurons lead to GABAergic neuron excitotoxicity. Furthermore, an inhibition of glutamate receptors partially reverses extracellular acidosis-induced dysfunctions of GABAergic neurons (Figs 7 and 8). Thus, in addition to the role of intracellular protons in GABAergic neuron dysfunction, the impairment of cortical astrocytes leads to glutamate-mediated excitotoxicity to the GABAergic neurons during acidosis (Fig 9).


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 dysfunction of glutamate transporter in the astrocyte leads to the impairment of GABAergic neuron during acidosis.Extracellular acidification impairs the function of astrocytic glutamate transporter (Glu-T), and the subsequent glutamate accumulation deteriorates GABAergic neurons through activating ionotropic glutamate receptors, such as NMDAR and AMPAR.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140324.g009: The dysfunction of glutamate transporter in the astrocyte leads to the impairment of GABAergic neuron during acidosis.Extracellular acidification impairs the function of astrocytic glutamate transporter (Glu-T), and the subsequent glutamate accumulation deteriorates GABAergic neurons through activating ionotropic glutamate receptors, such as NMDAR and AMPAR.
Mentions: We examined the involvement of cortical astrocytes in the acidosis-induced injury of GABAergic neurons. Extracellular acidosis impairs the GABAergic neurons in active intrinsic properties and synaptic outputs more severely, in comparison with intracellular acidosis (Figs 1–4). Extracellular acidosis also impairs cortical astrocytes in terms of the re-uptake of glutamates (Fig 5), which is associated with the enhanced glutamatergic synaptic transmission on the GABAergic neurons (Fig 6). These data indicate that astrocytic dysfunction in glutamate uptake and glutamatergic excitation in GABAergic neurons lead to GABAergic neuron excitotoxicity. Furthermore, an inhibition of glutamate receptors partially reverses extracellular acidosis-induced dysfunctions of GABAergic neurons (Figs 7 and 8). Thus, in addition to the role of intracellular protons in GABAergic neuron dysfunction, the impairment of cortical astrocytes leads to glutamate-mediated excitotoxicity to the GABAergic neurons during acidosis (Fig 9).

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