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Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons


Rapid information transfer within the brain depends on chemical signalling between neurons that is mediated primarily by glutamate and GABA (γ-aminobutyric acid), acting at ionotropic receptors to cause excitatory or inhibitory postsynaptic potentials (EPSPs or IPSPs), respectively. In addition, synaptically released glutamate acts on metabotropic receptors to excite neurons on a slower timescale through second-messenger cascades, including phosphoinositide hydrolysis1. We now report a unique IPSP mediated by the activation of metabotropic glutamate receptors. In ventral midbrain dopamine neurons, activation of metabotropic glutamate receptors (mGluR1) mobilized calcium from caffeine/ryanodine-sensitive stores and increased an apamin-sensitive potassium conductance. The underlying potassium conductance and dependence on calcium stores set this IPSP apart from the slow IPSPs described so far2,3,4. The mGluR-induced hyperpolarization was dependent on brief exposure to agonist, because prolonged application of exogenous agonist desensitized the hyperpolarization and caused the more commonly reported depolarization1,5,6. The rapid rise and brief duration of synaptically released glutamate in the extracellular space can therefore mediate a rapid excitation through activation of ionotropic receptors, followed by inhibition through the mGluR1 receptor. Thus the idea that glutamate is solely an excitatory neurotransmitter must be replaced with a more complex view of its dual function in synaptic transmission.

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Figure 1: The late component of the IPSP is mediated by mGluRs and activation of an apamin-sensitive potassium conductance.
Figure 2: The amplitude of mGluR IPSPs is increased by prior depolarization of the membrane potential.
Figure 3: The mGluR-mediated IPSP is dependent on intracellular Ca2+ stores.
Figure 4: Brief exogenous application of aspartate applied by pressure ejection mimics the IPSP.


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We thank O. J. Manzoni, P. Chavis, G. L. Westbrook and N. V. Marrion for comments on the manuscript. This work was supported by the National Institute on Drug Abuse.

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Correspondence to J. T. Williams.

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Fiorillo, C., Williams, J. Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature 394, 78–82 (1998).

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