D-Serine Contributes to Seizure Development via ERK Signaling
A seizure is one of the leading neurological disorders. NMDA receptor-mediated neuronal excitation has been thought to be essential for epileptogenesis. As an endogenous co-agonist of the NMDA receptor, D-serine has been suggested to play a role in epileptogenesis. However, the underlying mechanisms...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-03-01
|
| Series: | Frontiers in Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2019.00254/full |
| _version_ | 1818510714908704768 |
|---|---|
| author | Tie Ma Tie Ma Yin Wu Beibei Chen Wenjuan Zhang Lang Jin Chenxi Shen Yazhou Wang Yonghong Liu |
| author_facet | Tie Ma Tie Ma Yin Wu Beibei Chen Wenjuan Zhang Lang Jin Chenxi Shen Yazhou Wang Yonghong Liu |
| author_sort | Tie Ma |
| collection | DOAJ |
| description | A seizure is one of the leading neurological disorders. NMDA receptor-mediated neuronal excitation has been thought to be essential for epileptogenesis. As an endogenous co-agonist of the NMDA receptor, D-serine has been suggested to play a role in epileptogenesis. However, the underlying mechanisms remain unclear. In the current study, we investigated the effects of antagonizing two key enzymes in D-serine metabolism on the development of seizures and the downstream signaling. Our results showed that serine racemase (SR), a key enzyme in regulating the L-to-D-serine conversion, was significantly up-regulated in hippocampal astrocytes in rats and patients who experienced seizure, in comparison with control rats and patients. L-aspartic acid β-hydroxamate (LaaβH), an inhibitor of SR, significantly prolonged the latencies of seizures, shortened the durations of seizures, and decreased the total EEG power in rats. In contrast, D-amino acid oxidase inhibitor 5-chlorobenzo[d]isoxazol-3-ol (CBIO), which can increase D-serine levels, showed the opposite effects. Furthermore, our data showed that LaaβH and CBIO significantly affected the phosphorylation of Extracellular Signal-regulated Kinase (ERK). Antagonizing or activating ERK could significantly block the effects of LaaβH/CBIO on the occurrence of seizures. In summary, our study revealed that D-serine is involved in the development of epileptic seizures, partially through ERK signaling, indicating that the metabolism of D-serine may be targeted for the treatment of epilepsy. |
| first_indexed | 2024-12-10T23:23:46Z |
| format | Article |
| id | doaj.art-27475b3e7105419aa34ffdcfd4349824 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-10T23:23:46Z |
| publishDate | 2019-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-27475b3e7105419aa34ffdcfd43498242022-12-22T01:29:38ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-03-011310.3389/fnins.2019.00254438869D-Serine Contributes to Seizure Development via ERK SignalingTie Ma0Tie Ma1Yin Wu2Beibei Chen3Wenjuan Zhang4Lang Jin5Chenxi Shen6Yazhou Wang7Yonghong Liu8Department of Neurology, Xijing Hospital, Air Force Military Medical University, Xi’an, ChinaDepartment of Neurology, The Seventh Medical Center of PLA General Hospital, Beijing, ChinaDepartment of Pharmacy, Xi’an High-tech Hospital, Xi’an, ChinaDepartment of Neurology, Xijing Hospital, Air Force Military Medical University, Xi’an, ChinaDepartment of Neurology, Xijing Hospital, Air Force Military Medical University, Xi’an, ChinaDepartment of Neurology, Xijing Hospital, Air Force Military Medical University, Xi’an, ChinaDepartment of Neurology, Xijing Hospital, Air Force Military Medical University, Xi’an, ChinaDepartment of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Air Force Medical University, Xi’an, ChinaDepartment of Neurology, Xijing Hospital, Air Force Military Medical University, Xi’an, ChinaA seizure is one of the leading neurological disorders. NMDA receptor-mediated neuronal excitation has been thought to be essential for epileptogenesis. As an endogenous co-agonist of the NMDA receptor, D-serine has been suggested to play a role in epileptogenesis. However, the underlying mechanisms remain unclear. In the current study, we investigated the effects of antagonizing two key enzymes in D-serine metabolism on the development of seizures and the downstream signaling. Our results showed that serine racemase (SR), a key enzyme in regulating the L-to-D-serine conversion, was significantly up-regulated in hippocampal astrocytes in rats and patients who experienced seizure, in comparison with control rats and patients. L-aspartic acid β-hydroxamate (LaaβH), an inhibitor of SR, significantly prolonged the latencies of seizures, shortened the durations of seizures, and decreased the total EEG power in rats. In contrast, D-amino acid oxidase inhibitor 5-chlorobenzo[d]isoxazol-3-ol (CBIO), which can increase D-serine levels, showed the opposite effects. Furthermore, our data showed that LaaβH and CBIO significantly affected the phosphorylation of Extracellular Signal-regulated Kinase (ERK). Antagonizing or activating ERK could significantly block the effects of LaaβH/CBIO on the occurrence of seizures. In summary, our study revealed that D-serine is involved in the development of epileptic seizures, partially through ERK signaling, indicating that the metabolism of D-serine may be targeted for the treatment of epilepsy.https://www.frontiersin.org/article/10.3389/fnins.2019.00254/fullD-serineserine racemaseastrocyteepilepsyERKhippocampus |
| spellingShingle | Tie Ma Tie Ma Yin Wu Beibei Chen Wenjuan Zhang Lang Jin Chenxi Shen Yazhou Wang Yonghong Liu D-Serine Contributes to Seizure Development via ERK Signaling Frontiers in Neuroscience D-serine serine racemase astrocyte epilepsy ERK hippocampus |
| title | D-Serine Contributes to Seizure Development via ERK Signaling |
| title_full | D-Serine Contributes to Seizure Development via ERK Signaling |
| title_fullStr | D-Serine Contributes to Seizure Development via ERK Signaling |
| title_full_unstemmed | D-Serine Contributes to Seizure Development via ERK Signaling |
| title_short | D-Serine Contributes to Seizure Development via ERK Signaling |
| title_sort | d serine contributes to seizure development via erk signaling |
| topic | D-serine serine racemase astrocyte epilepsy ERK hippocampus |
| url | https://www.frontiersin.org/article/10.3389/fnins.2019.00254/full |
| work_keys_str_mv | AT tiema dserinecontributestoseizuredevelopmentviaerksignaling AT tiema dserinecontributestoseizuredevelopmentviaerksignaling AT yinwu dserinecontributestoseizuredevelopmentviaerksignaling AT beibeichen dserinecontributestoseizuredevelopmentviaerksignaling AT wenjuanzhang dserinecontributestoseizuredevelopmentviaerksignaling AT langjin dserinecontributestoseizuredevelopmentviaerksignaling AT chenxishen dserinecontributestoseizuredevelopmentviaerksignaling AT yazhouwang dserinecontributestoseizuredevelopmentviaerksignaling AT yonghongliu dserinecontributestoseizuredevelopmentviaerksignaling |