Lamotrigine inhibits postsynaptic AMPA receptor and glutamate release in the dentate gyrus.
OBJECTIVE
The dentate gyrus (DG) is a gateway that regulates seizure activity in the hippocampus. We investigated the site of action of lamotrigine (LTG), an effective anticonvulsant, in the regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptor-mediated excitatory synaptic transmission on DG.


METHODS
Evoked AMPA and NMDA receptor-mediated excitatory postsynaptic currents (eEPSCampa and eEPSCnmda) were recorded by whole-cell patch-clamp recording from the granule cells of DG in brain slice preparation of young Wistar rats (60-120 g). Exogenously applied AMPA and NMDA-induced currents and AMPA receptor-mediated miniature EPSC (mEPSCampa) were recorded in the presence of specific antagonists.


RESULTS
LTG inhibited both eEPSCampa and eEPSCnmda, and had no effect on exogenously applied NMDA-induced current indicating LTG inhibited glutamate release. Previous studies demonstrated that alteration in glutamate concentration in synaptic cleft causes parallel changes of eEPSCampa and eEPSCnmda. Our results showed that LTG inhibited eEPSCampa significantly more than eEPSCnmda (p < 0.05), suggesting that LTG may also have blocked the postsynaptic AMPA receptor. The hypothesis is further supported by the facts that; (1) LTG (30-100 microM) inhibited direct exogenously applied AMPA-induced currents (to 90%), (2) LTG significantly reduced the amplitude, but not the frequency of mEPSCampa and asynchronous (EPSC), and (3) LTG-induced reduction of eEPSCampa was not associated with a modification of the paired-pulse ratio. To sum up, LTG exerts a postsynaptic inhibitory mechanism on the AMPA receptor.


CONCLUSIONS
Our results demonstrate that LTG suppresses postsynaptic AMPA receptors and reduces glutamate release in granule cells of DG. The postsynaptic effect can be one of the underlying mechanisms of LTG's anticonvulsant action.
Lee
Chun-Yao
CY
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Fu
Wen-Mei
WM
Chen
Chih-Chuan
CC
Su
Ming-Jai
MJ
Liou
Horng-Huei
HH
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000188:drug therapy* / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D005971:Glutamates / Q000187:drug effects / Q000378:metabolism*; D000077213:Lamotrigine; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000819:agonists / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D005971:Glutamates; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000077213:Lamotrigine