Abstract
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that affects upper and lower motor neurons. Previous evidence has indicated that excitotoxic cell death in ALS may remarkably depend on Cl- ion influx through the GABAA receptors. In this study we have analysed the effect of Monocyte Chemoattractant Protein-1 (MCP-1), a chemokine expressed to a higher level in ALS patients, on GABAA receptors in cultured cortical neurons from a genetic model of ALS (G93A) and compared with wild type SOD1 (SOD1) and their corresponding non transgenic littermates (Control). By performing electrophysiological experiments we have observed that, in cortical neurons MCP-1 (2-150 ng/ml) induced an enhancement of GABA-evoked currents that was significantly higher in G93A neurons compared to controls. The effect of MCP-1 was not dependent on the activation of its receptor CCR2, while it was blocked by flumazenil, the antagonist of benzodiazepine sites. Analysis of GABAA receptor subunit composition has indicated an altered subunit expression level in G93A cortical neurons compared to controls. Instead, in cultured spinal neurons MCP-1 induced a significant reduction of GABA-evoked currents, also through the benzodiazepine sites, indicating a region-specific mechanism of action. However, no differences were observed in the current reduction between the three neuronal populations. These findings provide the first evidence that MCP-1, acting on benzodiazepine sites, can modulate the GABA-evoked currents, depending on the subunit composition of GABAA receptor. In cortical neurons MCP-1 upmodulates the GABA-evoked current and this effect is exacerbated in the mutated neurons. It is reasonable to assume that the higher Cl- influx through GABAA receptors in the presence of MCP-1 in mutated cortical neurons may induce an excitotoxicity acceleration. Agents able to block the MCP-1 production may then prove useful for ALS treatment.
| Original language | English |
|---|---|
| Pages (from-to) | 247-260 |
| Number of pages | 14 |
| Journal | Neuropharmacology |
| Volume | 73 |
| DOIs | |
| Publication status | Published - 2013 |
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Keywords
- ALS
- Electrophysiology
- GABA receptor modulator
- GABA-induced current
- Immunosystem
- Neurodegeneration
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Pharmacology
Cite this
Monocyte chemoattractant protein-1 upregulates gaba-induced current : Evidence of modified GABAA subunit composition in cortical neurons from the G93A mouse model of Amyotrophic Lateral Sclerosis. / Caioli, Silvia; Pieri, Massimo; Antonini, Alessia; Guglielmotti, Angelo; Severini, Cinzia; Zona, Cristina.
In: Neuropharmacology, Vol. 73, 2013, p. 247-260.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Monocyte chemoattractant protein-1 upregulates gaba-induced current
T2 - Evidence of modified GABAA subunit composition in cortical neurons from the G93A mouse model of Amyotrophic Lateral Sclerosis
AU - Caioli, Silvia
AU - Pieri, Massimo
AU - Antonini, Alessia
AU - Guglielmotti, Angelo
AU - Severini, Cinzia
AU - Zona, Cristina
PY - 2013
Y1 - 2013
N2 - Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that affects upper and lower motor neurons. Previous evidence has indicated that excitotoxic cell death in ALS may remarkably depend on Cl- ion influx through the GABAA receptors. In this study we have analysed the effect of Monocyte Chemoattractant Protein-1 (MCP-1), a chemokine expressed to a higher level in ALS patients, on GABAA receptors in cultured cortical neurons from a genetic model of ALS (G93A) and compared with wild type SOD1 (SOD1) and their corresponding non transgenic littermates (Control). By performing electrophysiological experiments we have observed that, in cortical neurons MCP-1 (2-150 ng/ml) induced an enhancement of GABA-evoked currents that was significantly higher in G93A neurons compared to controls. The effect of MCP-1 was not dependent on the activation of its receptor CCR2, while it was blocked by flumazenil, the antagonist of benzodiazepine sites. Analysis of GABAA receptor subunit composition has indicated an altered subunit expression level in G93A cortical neurons compared to controls. Instead, in cultured spinal neurons MCP-1 induced a significant reduction of GABA-evoked currents, also through the benzodiazepine sites, indicating a region-specific mechanism of action. However, no differences were observed in the current reduction between the three neuronal populations. These findings provide the first evidence that MCP-1, acting on benzodiazepine sites, can modulate the GABA-evoked currents, depending on the subunit composition of GABAA receptor. In cortical neurons MCP-1 upmodulates the GABA-evoked current and this effect is exacerbated in the mutated neurons. It is reasonable to assume that the higher Cl- influx through GABAA receptors in the presence of MCP-1 in mutated cortical neurons may induce an excitotoxicity acceleration. Agents able to block the MCP-1 production may then prove useful for ALS treatment.
AB - Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that affects upper and lower motor neurons. Previous evidence has indicated that excitotoxic cell death in ALS may remarkably depend on Cl- ion influx through the GABAA receptors. In this study we have analysed the effect of Monocyte Chemoattractant Protein-1 (MCP-1), a chemokine expressed to a higher level in ALS patients, on GABAA receptors in cultured cortical neurons from a genetic model of ALS (G93A) and compared with wild type SOD1 (SOD1) and their corresponding non transgenic littermates (Control). By performing electrophysiological experiments we have observed that, in cortical neurons MCP-1 (2-150 ng/ml) induced an enhancement of GABA-evoked currents that was significantly higher in G93A neurons compared to controls. The effect of MCP-1 was not dependent on the activation of its receptor CCR2, while it was blocked by flumazenil, the antagonist of benzodiazepine sites. Analysis of GABAA receptor subunit composition has indicated an altered subunit expression level in G93A cortical neurons compared to controls. Instead, in cultured spinal neurons MCP-1 induced a significant reduction of GABA-evoked currents, also through the benzodiazepine sites, indicating a region-specific mechanism of action. However, no differences were observed in the current reduction between the three neuronal populations. These findings provide the first evidence that MCP-1, acting on benzodiazepine sites, can modulate the GABA-evoked currents, depending on the subunit composition of GABAA receptor. In cortical neurons MCP-1 upmodulates the GABA-evoked current and this effect is exacerbated in the mutated neurons. It is reasonable to assume that the higher Cl- influx through GABAA receptors in the presence of MCP-1 in mutated cortical neurons may induce an excitotoxicity acceleration. Agents able to block the MCP-1 production may then prove useful for ALS treatment.
KW - ALS
KW - Electrophysiology
KW - GABA receptor modulator
KW - GABA-induced current
KW - Immunosystem
KW - Neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=84885169396&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84885169396&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2013.05.045
DO - 10.1016/j.neuropharm.2013.05.045
M3 - Article
VL - 73
SP - 247
EP - 260
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
ER -