Abstract
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.
Highlights
Epilepsy includes a group of neurological disorders characterized by loss of neurons and spontaneous occurrence of seizures
Because previous studies have reported that epilepsy induces astrocyte activation and that L-serine is primarily synthesized by astrocytes, we first examined the expression of D-serine after seizure induction by double immunostaining for GFAP and serine racemase (SR), a key enzyme that transforms L-serine into D-serine (Wolosker et al, 1999)
The results showed that, in the hippocampus, SR was expressed in both neurons and astrocytes
Summary
Epilepsy includes a group of neurological disorders characterized by loss of neurons and spontaneous occurrence of seizures. The underlying mechanisms remain to be fully elucidated, it has been widely accepted that N-methyl-D-aspartate receptor (NMDAR)-mediated neuronal hyperexcitation is essential for the development of epilepsy (Parsons and Raymond, 2014; Swanger et al, 2016; Rothan et al, 2017). D-serine acts as an allosteric modulator of the NMDAR channel by binding to the glycine site of the NMDAR (Kleckner and Dingledine, 1988; Schell et al, 1995). In both astrocytes and neurons, D-serine is converted from L-serine by serine racemase (SR). By agonizing NMDAR-mediated responses, D-serine plays important roles in the enhancement of synaptic functions and the maintenance of long term potentiation (Balu et al, 2013; Le Bail et al, 2015)
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