GAD65 deficient mice are susceptible to ethanol-induced impairment of motor coordination and facilitation of cerebellar neuronal firing.
γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter and its concentrations in the brain could be associated with EtOH-induced impairment of motor coordination. GABA is synthesized by two isoforms of glutamate decarboxylase (GAD): GAD65 and GAD67. Mice deficient in GAD65 (GAD65-KO) can...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0286031 |
| _version_ | 1797801995592007680 |
|---|---|
| author | Wataru Matsunaga Toru Shinoe Moritoshi Hirono |
| author_facet | Wataru Matsunaga Toru Shinoe Moritoshi Hirono |
| author_sort | Wataru Matsunaga |
| collection | DOAJ |
| description | γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter and its concentrations in the brain could be associated with EtOH-induced impairment of motor coordination. GABA is synthesized by two isoforms of glutamate decarboxylase (GAD): GAD65 and GAD67. Mice deficient in GAD65 (GAD65-KO) can grow up to adulthood, and show that GABA concentration in their adult brains was 50-75% that of wild-type C57BL/6 mice (WT). Although a previous study showed that there was no difference in recovery from the motor-incoordination effect of acute intraperitoneally administered injections of 2.0 g/kg EtOH between WT and GAD65-KO, the sensitivity of GAD65-KO to acute EtOH-induced ataxia has not been fully understood. Here, we sought to determine whether motor coordination and spontaneous firing of cerebellar Purkinje cells (PCs) in GAD65-KO are more sensitive to the effect of EtOH than in WT. Motor performance in WT and GAD65-KO was examined by rotarod and open-field tests following acute administration of EtOH at lower-doses, 0.8, 1.2 and 1.6 g/kg. In a rotarod test, there was no significant difference between WT and GAD65-KO in terms of baseline motor coordination. However, only the KO mice showed a significant decrease in rotarod performance of 1.2 g/kg EtOH. In the open-field test, GAD65-KO showed a significant increase in locomotor activity after 1.2 and 1.6 g/kg EtOH injections, but not WT. In in vitro studies of cerebellar slices, the firing rate of PCs was increased by 50 mM EtOH in GAD65-KO compared with WT, whereas no difference was observed in the effect of EtOH at more than 100 mM between the genotypes. Taken together, GAD65-KO are more susceptible to the effect of acute EtOH exposure on motor coordination and PC firing than WT. This different sensitivity could be attributed to the basal low GABA concentration in the brain of GAD65-KO. |
| first_indexed | 2024-03-13T04:59:02Z |
| format | Article |
| id | doaj.art-b6363bd9938a4100b84b3581451b5219 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-03-13T04:59:02Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b6363bd9938a4100b84b3581451b52192023-06-17T05:32:01ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01185e028603110.1371/journal.pone.0286031GAD65 deficient mice are susceptible to ethanol-induced impairment of motor coordination and facilitation of cerebellar neuronal firing.Wataru MatsunagaToru ShinoeMoritoshi Hironoγ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter and its concentrations in the brain could be associated with EtOH-induced impairment of motor coordination. GABA is synthesized by two isoforms of glutamate decarboxylase (GAD): GAD65 and GAD67. Mice deficient in GAD65 (GAD65-KO) can grow up to adulthood, and show that GABA concentration in their adult brains was 50-75% that of wild-type C57BL/6 mice (WT). Although a previous study showed that there was no difference in recovery from the motor-incoordination effect of acute intraperitoneally administered injections of 2.0 g/kg EtOH between WT and GAD65-KO, the sensitivity of GAD65-KO to acute EtOH-induced ataxia has not been fully understood. Here, we sought to determine whether motor coordination and spontaneous firing of cerebellar Purkinje cells (PCs) in GAD65-KO are more sensitive to the effect of EtOH than in WT. Motor performance in WT and GAD65-KO was examined by rotarod and open-field tests following acute administration of EtOH at lower-doses, 0.8, 1.2 and 1.6 g/kg. In a rotarod test, there was no significant difference between WT and GAD65-KO in terms of baseline motor coordination. However, only the KO mice showed a significant decrease in rotarod performance of 1.2 g/kg EtOH. In the open-field test, GAD65-KO showed a significant increase in locomotor activity after 1.2 and 1.6 g/kg EtOH injections, but not WT. In in vitro studies of cerebellar slices, the firing rate of PCs was increased by 50 mM EtOH in GAD65-KO compared with WT, whereas no difference was observed in the effect of EtOH at more than 100 mM between the genotypes. Taken together, GAD65-KO are more susceptible to the effect of acute EtOH exposure on motor coordination and PC firing than WT. This different sensitivity could be attributed to the basal low GABA concentration in the brain of GAD65-KO.https://doi.org/10.1371/journal.pone.0286031 |
| spellingShingle | Wataru Matsunaga Toru Shinoe Moritoshi Hirono GAD65 deficient mice are susceptible to ethanol-induced impairment of motor coordination and facilitation of cerebellar neuronal firing. PLoS ONE |
| title | GAD65 deficient mice are susceptible to ethanol-induced impairment of motor coordination and facilitation of cerebellar neuronal firing. |
| title_full | GAD65 deficient mice are susceptible to ethanol-induced impairment of motor coordination and facilitation of cerebellar neuronal firing. |
| title_fullStr | GAD65 deficient mice are susceptible to ethanol-induced impairment of motor coordination and facilitation of cerebellar neuronal firing. |
| title_full_unstemmed | GAD65 deficient mice are susceptible to ethanol-induced impairment of motor coordination and facilitation of cerebellar neuronal firing. |
| title_short | GAD65 deficient mice are susceptible to ethanol-induced impairment of motor coordination and facilitation of cerebellar neuronal firing. |
| title_sort | gad65 deficient mice are susceptible to ethanol induced impairment of motor coordination and facilitation of cerebellar neuronal firing |
| url | https://doi.org/10.1371/journal.pone.0286031 |
| work_keys_str_mv | AT watarumatsunaga gad65deficientmicearesusceptibletoethanolinducedimpairmentofmotorcoordinationandfacilitationofcerebellarneuronalfiring AT torushinoe gad65deficientmicearesusceptibletoethanolinducedimpairmentofmotorcoordinationandfacilitationofcerebellarneuronalfiring AT moritoshihirono gad65deficientmicearesusceptibletoethanolinducedimpairmentofmotorcoordinationandfacilitationofcerebellarneuronalfiring |