Selective reduction by dopamine of excitatory synaptic inputs to pyramidal neurons in primate prefrontal cortex

Abstract

We have employed in vitro physiological methods to investigate dopaminergic modulation of excitatory synaptic transmission in monkey prefrontal cortex (PFC) circuits. We show that combined activation of D1-like and D2-like dopamine receptors results in the reduction of extracellular stimulation-evoked isolated EPSCs in layer 3 pyramidal neurons. Using paired recordings from synaptically connected pyramidal neurons we have determined the basic properties of unitary synaptic connections between layer 3 pyramids in the primate PFC and, interestingly, we found that dopamine does not reduce synaptic transmission between nearby pairs of synaptically coupled PFC pyramidal neurons. This input specificity may be a critical aspect of the dopaminergic regulation of recurrent excitatory circuits in the PFC.

Figure 1. DA depresses extracellular stimulation-evoked EPSCs in layer 3 pyramidal cells of the monkey PFC

A, axons from several sources travel in the superficial layers of the PFC and form excitatory synapses onto layer 3 pyramidal neurons. Extracellular stimulation in superficial layers of the PFC may activate axons that originate in the contralateral PFC (callosal), the dorsomedial thalamus (thalamic), or from the cortex (long range cortical, either the PFC or other cortical areas which project to the PFC). Extracellular stimulation also may activate synapses made by pyramidal cells within 100–200 μm of the recorded cell via an anti/ortho-dromic route (short range cortical). B, extracellular stimulation-evoked postsynaptic currents (PSCs) were screened to obtain isolated EPSCs. Only PSCs showing no evidence of outward current at holding potentials positive to the chloride reversal potential were selected. Dopamine reduced the amplitude of isolated EPSCs. C, time course showing the average effect of dopamine (1–5 μm) on the peak amplitude of isolated extracellular stimulation-evoked EPSCs.

Figure 2. Pharmacology of the reduction of EPSCs in layer 3 pyramidal cells

Bar graph showing the effects of various DA agonists and antagonists (concentrations in micromolar) on the amplitude of extracellular stimulation-evoked EPSCs recorded in layer 3 pyramidal neurons. *P > 0.05 when compared to control.

Figure 3. Excitatory connections between nearby layer 3 pyramidal neurons are unaffected by addition of DA

A, left, schematic showing recording configuration. Two pyramidal neurons with somata less than 50 μm apart were recorded simultaneously. Right, activation of an action potential in one cell evoked a unitary EPSP in the other. Traces show average pre- and postsynaptic responses from 10 consecutive sweeps recorded under control conditions (black line - a) or in the presence of dopamine (5 μm, grey line - b). B, time course of the DA effect. The amplitude of each unitary EPSP is plotted as a function of time from whole cell break-in. DA had no observable effect on EPSP amplitude at this unitary connection. Markings (a) and (b) show the time at which example traces in A were recorded. C, histogram showing amplitudes of the unitary EPSPs recorded in control conditions and in the presence of DA. D, group data showing effect of DA application on unitary EPSPs.