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.