Up-regulation of d-serine Might Induce GABAergic Neuronal Degeneration in the Cerebral Cortex and Hippocampus in the Mouse Pilocarpine Model of Epilepsy

Abstract

Epilepsy is a serious neurological disorder with neuronal loss and spontaneous recurrent seizures, but the neurochemical basis remains largely unclear. We hypothesize that D-serine, a newly identified endogenous co-agonist of N-methyl-D-aspartate (NMDA) receptor, may trigger excitotoxicity and neuronal damage in epileptogenesis. By using a mouse pilocarpine model, immunohistochemistry, Fluoro-Jade staining and double-labeling, the present study revealed up-regulation of D-serine expression in a proportion (41%) of neurons in the cerebral cortex and hippocampus. The D-serine-positive neurons occurred at 4 h, reached peak levels at 12-24 h, and gradually went down at 3-14 days. Moreover, most of D-serine-positive neurons were GABAergic (98%), underwent degenerating death (93%), and were accompanied enhancing phosphorylation of NMDA receptor subunit 1. This study has provided new evidence that up-regulation of D-serine production might induce GABAergic neuronal degeneration through excitotoxic mechanism in the pilocarpine model and may be involved in early pathogenesis and recurrent seizure of chronic epilepsy.

Subacute administration of fluoxetine prevents short-term brain hypometabolism and reduces brain damage markers induced by the lithium-pilocarpine model of epilepsy in rats

“…In addition, d-serine, a recently identified endogenous co-agonist of NMDA receptor , may trigger excitotoxicity and neuronal damage in epileptogenesis. By using the pilocarpine model in mice, it has been shown up-regulation of d-serine expression in a large proportion of neurons in cortex and hippocampus but not in other brain regions (Liu et al, 2009). This study revealed that most of d-serine-positive neurons were GABAergic (98%), underwent degenerating death (93%), and were accompanied enhancing phosphorylation of NMDA receptor subunit 1.…”

“…These findings suggest that d-serine signaling cascades may be involved in the selective death of GABAergic neurons through NMDA receptor over-activation and excitotoxicity following pilocarpine insult. Furthermore, Liu et al (2009) proposed that those events may be involved in early pathogenesis and recurrent seizures associated with chronic epilepsy.…”

D‐serine is distributed in neurons in the brain of the sea lamprey

“…Together, these results indicate that colocalization of D-serine with GABA (as with colocalization of glycine with GABA) is specific to some neuronal populations. In rodents, the presence of D-serine in some GABAergic cells has only recently been reported for the cerebral cortex and hippocampus in a mouse pilocarpine model of epilepsy (Liu et al, 2009). The presence of D-serine in numerous GABAergic cells and, possibly, in some glycinergic cells suggests that many of the D-serinecontaining brain neurons in lamprey are inhibitory cells in which D-serine would contribute putatively to local modulation of neighboring cells and processes.…”

“…Brain levels of D-serine appear to modulate important brain functions, and the control of D-serine level in the brain may be important for neuroprotection against various neurodegenerative diseases (Inoue et al, 2009;Liu et al, 2009). Brain D-serine is synthesized mostly by the enzyme serine racemase, which converts L-serine to D-serine in a highly selective manner (Dunlop and Neidle, 1997;Wolosker et al, 1999;De Miranda et al, 2002), whereas the enzyme D-amino acid oxidase (DAO) is involved in the elimination of free serine (Nagata, 1992).…”

Time Course of Postnatal Distribution of Doublecortin Immunoreactive Developing/Maturing Neurons in the Somatosensory Cortex and Hippocampal CA1 Region of C57BL/6 Mice

“…The hippocampus, a part of limbic system in the brain, is involved in memory formation and affective state. In addition, this region is associated with some brain diseases such as seizure, ischemia, and Alzheimer's disease (Hwang et al 2009;Liu et al 2009). Recently, this region has received additional attention because neurogenesis occurs in the hippocampal dentate gyrus throughout life (Eriksson et al 1998;Gage et al 1998;McDonald and Wojtowicz 2005).…”