NMDA depresses glutamatergic synaptic transmission in the striatum through the activation of adenosine A1 receptors: evidence from knockout mice.
N-methyl-D-aspartate (NMDA) receptors play several essential roles in the physiology and pathophysiology of the brain. Their activation results in long-term changes in glutamatergic synaptic transmission in several brain areas, but excessive activation of these receptors induces neurotoxicity. Some of NMDA-mediated actions are critically dependent on functional interactions with the neuromodulator adenosine. In the present study, we have examined whether pharmacological activation of NMDA receptors induces long-term changes in synaptic strength in the striatum. We found that NMDA depressed the amplitude of the field excitatory postsynaptic potential/population spike (fEPSP/PS) recorded in corticostriatal mouse brain slices in a concentration-dependent manner. Inhibition of synaptic transmission was more pronounced at room temperature (22 degrees C) than at 32 degrees C and long lasting (> 2 h) depression of the fEPSP/PS was observed only at room temperature. NMDA-induced depression of the fEPSP/PS was reduced or abolished in the presence of an A1 receptor antagonist and in A1 receptor knockout mice. In addition, exogenous application of adenosine depressed fEPSP/PS amplitude in wild-type mice, but not in A1 receptor knockout mice, in a concentration-dependent manner. Our results demonstrate that NMDA depresses synaptic transmission in a concentration- and temperature-dependent manner via release of adenosine and activation of adenosine A1 receptors.
Schotanus
Sietske M
SM
The Karolinska Institute, Department of Physiology and Pharmacology, Section of Molecular Neurophysiology, Von Eulers Väg 8, 171 77 Stockholm, Sweden.
Fredholm
Bertil B
BB
Chergui
Karima
K
D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D003342:Corpus Striatum / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000502:physiology*; D009435:Synaptic Transmission; D013696:Temperature
D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate