RT Journal Article
SR Electronic
T1 D<sub>1</sub>/D<sub>5</sub> Dopamine Receptor Activation Differentially Modulates Rapidly Inactivating and Persistent Sodium Currents in Prefrontal Cortex Pyramidal Neurons
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2268
OP 2277
DO 10.1523/JNEUROSCI.21-07-02268.2001
VO 21
IS 7
A1 Nicolas Maurice
A1 Tatiana Tkatch
A1 Miriam Meisler
A1 Leslie K. Sprunger
A1 D. James Surmeier
YR 2001
UL http://www.jneurosci.org/content/21/7/2268.abstract
AB 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 D1 DA receptor activation. Several studies have argued that D1 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 D1 or D5 DA receptors consistently suppressed rapidly inactivating Na+ currents in identified corticostriatal pyramidal neurons. This modulation was attenuated by a D1/D5 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 D1/D5 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 α-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 D1/D5 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.