References

Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits

Gao, Krimer, Goldman-Rakic; PNAS 98-1, 295-300, 2001.

The prefrontal cortex plays a fundamental role in the working memory functions of the cerebral cortex and is also the site of dysfunction in several neurological and psychiatric disorders, including schizophrenia. Prefrontal neurons are distinguished by their capacity for sustained activity during the time a stimulus is held in memory, and this mnemonic response is considered a substrate for a variety of cognitive functions. The neuronal basis for sustained activity in prefrontal neurons is unknown but is thought to involve recurrent excitation among pyramidal neurons. Recent studies in awake behaving monkeys have demonstrated that the persistent activity in prefrontal neurons is modulated by dopamine. To examine the mechanisms by which dopamine might modulate transmission in local excitatory circuits, we have performed dual whole-cell recordings in connected pyramidal cell pairs with and without dopamine application. We find that dopamine reduces the efficacy of unitary excitatory neurotransmission in layer V pyramidal cells by decreasing its reliability. These effects, which are reproduced by a selective D1 agonist and blocked by a D1 antagonist, are independent of voltage changes and are not attenuated by blockade of sodium and potassium channels in the postsynaptic neurons. We conclude that attenuation of local horizontal excitatory synaptic transmission in layer V pyramidal neurons by dopamine is through D1 actions at a presynaptic site.

The prefrontal cortex (PFC) plays a primary role in working memory, the mental operation critical for “online” processing of information (1, 2). Prefrontal neurons exhibit persistent neuronal firing throughout the delay interval intervening between a stimulus and a memory-guided response. Understanding the cellular and circuit basis of sustained neural activity maintained in the absence of a stimulus is considered an important quest in cognitive neuroscience (2). Previous studies in this laboratory have revealed a role for dopamine (DA) acting at D1 receptors in the modulation of a prefrontal neuron's excitatory response to its preferred stimulus (3). The sustained response of prefrontal neurons in the absence of a stimulus has generated considerable interest (4–11), but the precise pharmacological and circuit mechanisms underlying this activation remain unclear. As DA terminals and glutamatergic terminals form so-called synaptic triads with dendritic spines of pyramidal neurons (12, 13), we have proposed that DA directly modulates glutamate transmission at such triads, and thereby is a modulator of recurrent excitatory interactions between and among local pyramidal neurons that could promote persistent neural activity. To directly test this hypothesis, we have examined the synaptic effects of DA on recurrent excitatory transmission between pairs of pyramidal neurons by means of dual whole-cell patch clamp recording combined with DA application. In particular, we have examined DA's effects on unitary excitatory postsynaptic potentials (EPSPs), especially DA's modulation of glutamate release and whether pre- or postsynaptic mechanisms are involved. Our results indicate that DA directly reduces the probability of glutamate release in layer V pyramidal neurons by D1 actions at a presynaptic site. These results provide a possible neurophysiological basis for understanding the interaction of DA and glutamate in the pathophysiology and treatment of schizophrenia.

Web Resource: www.pnas.org

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Keywords: recurrent excitation, feedback, dopamine, D1, PFC