L-trans-PDC enhances hippocampal neuronal activity by stimulating glial glutamate release independently of blocking transporters.
The glutamate transporter inhibitor, L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) reversibly enhanced hippocampal neuronal activity in the rat and mouse dentate gyrus. The PDC action was still found in mice lacking the glial glutamate transporter GLT-1. PDC did not influence the rate of spontaneous miniature excitatory postsynaptic currents and spontaneous inhibitory postsynaptic currents, ionotropic glutamate receptor currents, or GABA-evoked currents in cultured rat hippocampal neurons. PDC increased glutamate released from cultured hippocampal astrocytes from normal rats, normal mice, and GLT-1 knock-out mice, that is not inhibited by deleting extracellular Na(+), while the drug had no effect on the release from cultured rat hippocampal neurons. The results of the present study thus suggest that PDC stimulates glial glutamate release by a mechanism independent of inhibiting glutamate transporters, which perhaps causes an increase in synaptic glutamate concentrations, in part responsible for the enhancement in hippocampal neuronal activity.
Ohta
Kohei
K
Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.
Nomura
Tamotsu
T
Kanno
Takeshi
T
Nagai
Kaoru
K
Yamamoto
Satoshi
S
Yajima
Yukio
Y
Kondoh
Takeshi
T
Kohmura
Eiji
E
Saito
Naoaki
N
Nishizaki
Tomoyuki
T
D000818:Animals; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D013570:Synaptic Membranes / Q000502:physiology
D003998:Dicarboxylic Acids; D011759:Pyrrolidines; D018698:Glutamic Acid; C083486:pyrrolidine-2,4-dicarboxylic acid