Vignesh Subramanian ’24

Temporal lobe epilepsy (TLE) is the most common form of both focal epilepsy – the recurrence of seizures in one hemisphere of the brain – and drug resistant epilepsy. The disease is characterized by neuronal cell death in Layer 3 (L3) of the medial entorhinal area (MEA), the internal region of the temporal lobe constituting memory and higher-order cognitive functioning. Recent studies have revealed that excitatory postsynaptic currents (EPSC) in the MEA region are mediated by proteins known as N-methyl-D-aspartate receptors (NMDARs), which either have a significant affinity for magnesium ions (as conventional d-NMDARs do) or are highly permeable to calcium ions (as t-NMDARs are); these ions enable electrical conduction and maintain synaptic plasticity, respectively. An amino acid known as D-serine is particularly capable of promoting d-NMDAR responses as an agonist and blocking t-NMDAR responses as an antagonist, suggesting it could counteract excitotoxicity at such receptors. To better understand the EPSC and neuroinflammation suppression capabilities of D-serine, a study at the Florida State University College of Medicine thus explored whether TLE-associated neuronal loss could be reduced by the gliotransmitter’s application.

Researchers first osmotically administered D-serine via surgically implanted pumps to cannulated adult rats that had undergone a pilocarpine-induced seizure, monitoring subjects post-epileptic attack for recurrence with seizure severity being scored on a modified Racine scale. The animals’ brains were then harvested to allow for histological correlation of neuronal loss with behaviorally observed changes, while Nissl staining protocols and assays of the cells’ final arborization enabled stereological and morphological analysis of overlapping neuron and astrocyte cell counts, respectively. 

Researchers found that recorded neuronal loss preceded the epileptic attack – establishing it as a cause – and that D-serine infusion both significantly attenuated neuronal loss and was inversely correlated with an upregulated astrocytic signal, suggesting D-serine’s anti-inflammatory capabilities could limit the need for defensive processes such as astrogliosis to occur. Further testing involving chiral micellar electrokinetic chromatography confirmed the reduction in D-serine levels and ensuing failure to mediate calcium ion influx-induced excitotoxicity at t-NMDAR sites.

The findings of this study collectively identify the previously unknown impact of D-serine release on the mitigation of epileptogenesis, with a particular emphasis on the amino acid’s counteraction of gliosis and postsynaptic antagonization of t-NMDARs. Further research might be aimed at determining whether astrocytes are truly involved in the synthesis of D/L-serine and prophylaxis of status epilepticus and/or the prognosis of TLE itself.

Works Cited

[1] S. Kumar, et al., D-serine mitigates cell loss associated with temporal lobe epilepsy. Nature Communications 11, 4966 (2020). doi: 10.1038/s41467-020-18757-2

[2] Image retrieved from: https://radiopaedia.org/articles/entorhinal-cortex