D1/D5 dopamine receptor activation differentially modulates rapidly inactivating and persistent sodium currents in prefrontal cortex pyramidal neurons.
Dopamine (DA) is a well established modulator of prefrontal cortex (PFC) function, yet the cellular mechanisms by which DA exerts its effects in this region are controversial. A major point of contention is the consequence of D(1) DA receptor activation. Several studies have argued that D(1) receptors enhance the excitability of PFC pyramidal neurons by augmenting voltage-dependent Na(+) currents, particularly persistent Na(+) currents. However, this conjecture is based on indirect evidence. To provide a direct test of this hypothesis, we combined voltage-clamp studies of acutely isolated layer V-VI prefrontal pyramidal neurons with single-cell RT-PCR profiling. Contrary to prediction, the activation of D(1) or D(5) DA receptors consistently suppressed rapidly inactivating Na(+) currents in identified corticostriatal pyramidal neurons. This modulation was attenuated by a D(1)/D(5) receptor antagonist, mimicked by a cAMP analog, and blocked by a protein kinase A (PKA) inhibitor. In the same cells the persistent component of the Na(+) current was unaffected by D(1)/D(5) receptor activation-suggesting that rapidly inactivating and persistent Na(+) currents arise in part from different channels. Single-cell RT-PCR profiling showed that pyramidal neurons coexpressed three alpha-subunit mRNAs (Nav1.1, 1.2, and 1.6) that code for the Na(+) channel pore. In neurons from Nav1.6 null mice the persistent Na(+) currents were significantly smaller than in wild-type neurons. Moreover, the residual persistent currents in these mutant neurons-which are attributable to Nav1.1/1.2 channels-were reduced significantly by PKA activation. These results argue that D(1)/D(5) DA receptor activation reduces the rapidly inactivating component of Na(+) current in PFC pyramidal neurons arising from Nav1.1/1.2 Na(+) channels but does not modulate effectively the persistent component of the Na(+) current that is attributable to Nav1.6 Na(+) channels.
Department of Physiology/Institute for Neuroscience, Northwestern University Medical School, Chicago, Illinois 60611, USA.
N
N
Maurice
T
T
Tkatch
M
M
Meisler
L K
LK
Sprunger
D J
DJ
Surmeier
D000818:Animals; D051379:Mice; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D050641:Receptors, Dopamine D5; D012964:Sodium / Q000502:physiology*; D015222:Sodium Channels / Q000502:physiology*
C493606:Drd5 protein, mouse; C493607:Drd5 protein, rat; D017447:Receptors, Dopamine D1; D015222:Sodium Channels; D050641:Receptors, Dopamine D5; D012964:Sodium