Glycine transporter 1 is a target for the treatment of epilepsy

Abstract

Glycine is the major inhibitory neurotransmitter in brainstem and spinal cord, whereas in hippocampus glycine exerts dual modulatory roles on strychnine-sensitive glycine receptors and on the strychnine-insensitive glycineB site of the N-methyl-D-aspartate receptor (NMDAR). In hippocampus, the synaptic availability of glycine is largely under control of glycine transporter 1 (GlyT1). Since epilepsy is a disorder of disrupted network homeostasis affecting the equilibrium of various neurotransmitters and neuromodulators, we hypothesized that changes in hippocampal GlyT1 expression and resulting disruption of glycine homeostasis might be implicated in the pathophysiology of epilepsy. Using two different rodent models of temporal lobe epilepsy (TLE) – the intrahippocampal kainic acid model of TLE in mice, and the rat model of tetanic stimulation-induced TLE – we first demonstrated robust overexpression of GlyT1 in the hippocampal formation, suggesting dysfunctional glycine signaling in epilepsy. Overexpression of GlyT1 in the hippocampal formation was corroborated in human TLE samples by quantitative real time PCR. In support of a role of dysfunctional glycine signaling in the pathophysiology of epilepsy, both the genetic deletion of GlyT1 in hippocampus and the GlyT1 inhibitor LY2365109 increased seizure thresholds in mice. Importantly, chronic seizures in the mouse model of TLE were robustly suppressed by systemic administration of the GlyT1 inhibitor LY2365109. We conclude that GlyT1 overexpression in the epileptic brain constitutes a new target for therapeutic intervention, and that GlyT1 inhibitors constitute a new class of antiictogenic drugs. These findings are of translational value since GlyT1 inhibitors are already in clinical development to treat cognitive symptoms in schizophrenia.

Glial Na+‐dependent ion transporters in pathophysiological conditions

“…This increase in astrocyte Na + can have a dual effect, since it may increase NMDA receptor mediated excitation, but at higher concentrations it can also induce an inhibitory effect mediated by glycine receptor activation. Glyt1 blockade was recently shown to inhibit epileptic activity (Shen et al, ) suggesting that elevated extracellular glycine levels may overall inhibit seizures. Finally, Na + increase in astrocytes can trigger the reversal of the Na + /Ca 2+ exchanger, effectively allowing Ca 2+ to enter the astrocyte (Kirischuk et al, ), thereby linking Na + entry to the Ca 2+ ‐dependent mechanisms.…”

Spinal cord injury and its underlying mechanism in rats with temporal lobe epilepsy

“…In addition, the mechanism underlying epilepsies-mediated injury remains to be investigated. Our previous study investigated severe neuronal injury, damage to the blood-brain barrier (BBB) and neuronal uptake of serum albumin in the brain parenchyma of a kainic acid (KA)-induced rat model of temporal lobe epilepsy (TLE) (7,8). The present study aimed to investigate the pathological changes and underlying mechanisms of spinal cord injury in TLE.…”

“…Another previous study showed that after seizure, the expression levels of serum C-response protein, cytokines and inflammatory factors are markedly increased, thus indicating a systemic seizure-associated inflammatory reaction (6). The brain and spinal cord share a common origin, which is supported by the co-expression of specific neurotransmitters in both locations (7,8). Therefore, there may be a close connection between spinal cord injury and the abnormal discharge of brain neurons (7,8).…”

“…The brain and spinal cord share a common origin, which is supported by the co-expression of specific neurotransmitters in both locations (7,8). Therefore, there may be a close connection between spinal cord injury and the abnormal discharge of brain neurons (7,8).…”

Does rapid and physiological astrocyte–neuron signalling amplify epileptic activity?

“…Glyt1 blockade was recently shown to inhibit epileptic activity (Shen et al . ) suggesting that elevated extracellular glycine levels may overall inhibit epileptic activity. Finally, a Na + increase can trigger the reversal of the Na + /Ca 2+ exchanger effectively allowing Ca 2+ to enter the astrocyte (Kirischuk et al .…”