The Cortical Dopamine System: Role in Memory and Cognition

There are three distinct possible cellular mechanisms that have so far been identified for dopamine modulation of working memory function in the prefrontal cortex. These are: direct synaptic modulation of receptors on the distal dendrites and spines of pyramidal neurons, direct nonsynaptic modulation of pyramidal neurons, and indirect synaptic modulation of pyramidal neurons via feedforward inhibition from GABAergic interneurons. As the majority of the dopamine synapses appear to be formed on pyramidal neurons, dopamine axons are thus placed in direct contact with the major projection neurons of the prefrontal cortex. Nonsynaptic neurotransmission may be the more pervasive means of altering pyramidal cell activity, because numerous dopamine varicosities are observed in nonsynaptic relationship to cortical elements. Members of the D1 family of dopamine receptors have been found to be particularly prominent in the prefrontal cortex of primates, and both D1 and D5 receptor proteins have been localized to the distal dendrites and spines of pyramidal cells. A third mechanism of dopamine action is indirect, appearing to involve feedforward inhibition on pyramidal neurons from nonpyramidal neurons. The indirect action of dopamine on this circuit derives from the identification of dopamine synapses on nonpyramidal GABAergic neurons in the prefrontal cortex and the finding that the D4 member of the D2 family of dopamine receptors is localized postsynaptically on a subset of GABA interneurons. These findings provide suggestive evidence that feedforward inhibition may play a role in the construction of a memory field in prefrontal neurons. The different effects of dopamine may depend on the subtype of interneuron engaged, and future studies may indicate the basis for the differential modulation of interneurons by dopamine.