Keywords
D-serine
N-methyl-D-aspartate Receptor
Seizure Modulation
Epilepsy
Neurometabolism
Abstract
The modulation of excitatory neurotransmission remains a critical frontier in the management of drug-resistant epilepsy. Traditional anti-seizure medications primarily target ion channels or enhance inhibitory gamma-aminobutyric acid signaling, yet a significant proportion of patients continue to experience spontaneous recurrent seizures. This paper explores an alternative paradigm: the targeted suppression of the astrocytic L-serine biosynthesis pathway to reduce N-methyl-D-aspartate receptor overactivation. Specifically, the research investigates the inhibition of phosphoserine phosphatase, the terminal enzyme in the de novo serine synthesis pathway. By suppressing phosphoserine phosphatase, the availability of L-serine, and consequently its downstream product D-serine, is significantly reduced. D-serine functions as an essential co-agonist at the N-methyl-D-aspartate receptor, and its attenuation provides a novel mechanism for mitigating excitotoxicity and network hyperexcitability. This comprehensive study details the theoretical foundations of the serine shuttle, the methodology for implementing both genetic and pharmacological phosphoserine phosphatase inhibition in established seizure models, and the resulting electrophysiological and biochemical alterations. Findings indicate that phosphoserine phosphatase inhibition effectively modulates seizure frequency and amplitude while maintaining basal synaptic transmission. The mechanisms underlying these effects, along with potential compensatory metabolic pathways and therapeutic implications, are thoroughly analyzed. The results advocate for metabolic enzyme modulation as a viable strategy for seizure suppression, expanding the therapeutic landscape for neurological disorders characterized by glutamatergic hyperactivity.References
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