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.