Abstract
The persistent Na+ current (INap) is believed to be an important target of dopamine modulation in prefrontal cortex (PFC) neurons. While past studies have tested the effects of dopamine on INap, the results have been contradictory largely because of difficulties in measuring INap using somatic whole-cell recordings. To circumvent these confounds we used the cell-attached patch-clamp technique to record single Na+ channels from the soma, proximal dendrite (PD) or proximal axon (PA) of intact prefrontal layer V pyramidal neurons. Under baseline conditions, numerous well resolved Na+ channel openings were recorded that exhibited an extrapolated reversal potential of 73 mV, a slope conductance of 14–19 pS and were blocked by tetrodotoxin (TTX). While similar in most respects, the propensity to exhibit prolonged bursts lasting >40 ms was many fold greater in the axon than the soma or dendrite. Bath application of the D1/D5 receptor agonist SKF81297 shifted the ensemble current activation curve leftward and increased the number of late events recorded from the PD but not the soma or PA. However, the greatest effect was on prolonged bursting where the D1/D5 receptor agonist increased their occurrence 3 fold in the PD and nearly 7 fold in the soma, but not at all in the PA. As a result, D1/D5 receptor activation equalized the probability of prolonged burst occurrence across the proximal axosomatodendritic region. Therefore, D1/D5 receptor modulation appears to be targeted mainly to Na+ channels in the PD/soma and not the PA. By circumventing the pitfalls of previous attempts to study the D1/D5 receptor modulation of INap, we demonstrate conclusively that D1/D5 receptor activation can increase the INap generated proximally, however questions still remain as to how D1/D5 receptor modulates Na+ currents in the more distal initial segment where most of the INap is normally generated.
Highlights
Dopamine modulates a number of cognitive functions mediated by the prefrontal cortex (PFC) while dysregulation of the mesocortical dopamine system is thought to occur in psychiatric conditions
The present study investigated the effects of the D1/D5 receptor agonist SKF81297 on single Na+ channel gating recorded from the proximal dendrite (PD), soma and proximal axon (PA) of deep layer medial prefrontal cortex (mPFC) neurons in acute brain slices
We found that SKF81297 shifted the activation of the early transient channel openings to more negative potentials in all three regions, while increasing the Po of late openings and increasing prolonged burst probability mainly in the PD and to lesser extent in the soma
Summary
Dopamine modulates a number of cognitive functions mediated by the prefrontal cortex (PFC) while dysregulation of the mesocortical dopamine system is thought to occur in psychiatric conditions. A number of studies have reported that dopamine modulates INap in PFC neurons but the issue has been quite contentious. The inconsistencies may stem largely from the limitations of the techniques commonly used to study INap. In the initial papers, sharp intracellular pipettes were used (Geijo-Barrientos and Pastore, 1995; Yang and Seamans, 1996) which create a considerable shunt around the electrode and extremely poor voltage control. Given the diameter of the axon relative to the soma, if the axon is >10 um in length, it’s voltage is still difficult to control from a somatic electrode (White et al, 1995) while a second drawback is that key intracellular cascades could be disrupted or lost in the dissociation procedure which could be potentially serious given the dramatic differences in INap in the presence vs absence of Frontiers in Neural Circuits www.frontiersin.org
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