Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits

Abstract

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. T he 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...

Dopaminergic Regulation of Inhibitory and Excitatory Transmission in the Basolateral Amygdala–Prefrontal Cortical Pathway

“…Second, D 1 receptor activation attenuates both excitatory responses in the mPFC evoked by local stimulation and BLA-evoked responses in the NAc via a presynaptic mechanism (Floresco et al, 2001;Gao et al, 2001;Seamans et al, 2001a;Charara and Grace, 2003;Mair and Kauer, 2007). Furthermore, we observed a dramatic alteration in the paired-pulse ratio of BLA-evoked firing after VTA stimulation, which suggests a presynaptic mode of action (Fig.…”

Dopamine D1 and D4 Receptor Subtypes Differentially Modulate Recurrent Excitatory Synapses in Prefrontal Cortical Pyramidal Neurons

“…This is consistent with studies showing that DA acts on D1/D5 receptors to enhance intracortically evoked EPSCs in layer II/III (Gonzalez-Islas and Hablitz, 2003) and layer V pyramidal neurons of rat PFC (Seamans et al, 2001a), without affecting mini-EPSCs (Zhou and Hablitz, 1999), that is, a direct postsynaptic action on the pyramidal neuron. In contrast, studies using paired-neuron stimulation/recordings suggest that D1 receptors may produce an inhibitory response via attenuation of excitatory transmission in the ferret (Gao et al, 2001) and in the primate (with coactivation of D2 receptors, Urban et al, 2002). Although our data do not directly address pre-vs postsynaptic events, the D1 enhancement of the late Figure 9 D4 antagonist administration produces little enhancement of both membrane excitability and short latency-evoked responses in Type I pyramidal neurons in which relatively few axon collaterals were preserved in slices ( Figure 2 a3; b2).…”

Comparison of the Inhibitory and Excitatory Effects of ADHD Medications Methylphenidate and Atomoxetine on Motor Cortex

“…Studies in cats (Huda et al, 2001) and rodents (Awenowicz and Porter, 2002) have demonstrated reduced excitability in motor neurons, which produce the MEP to TMS, after application of DA. A recent study in monkey prefrontal cortex showed that DA decreases horizontal excitatory transmission in cortical layer 5 by a D1 receptormediated mechanism (Gao et al, 2001). Such horizontal excitatory connections in the motor cortex are likely involved in the amplification of excitatory signals that results in the MEP after TMS.…”