Dopamine D1/5 Receptor-Mediated Long-Term Potentiation of Intrinsic Excitability in Rat Prefrontal Cortical Neurons: Ca2+-Dependent Intracellular Signaling

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Abstract
Prefrontal cortex (PFC) dopamine D1/5 receptors modulate long- and short-term neuronal plasticity that may contribute to cognitive functions. Synergistic to synaptic strength modulation, direct postsynaptic D1/5 receptor activation also modulates voltage-dependent ionic currents that regulate spike firing, thus altering the neuronal input–output relationships in a process called long-term potentiation of intrinsic excitability (LTP-IE). Here, the intracellular signals that mediate this D1/5 receptor-dependent LTP-IE were determined using whole cell current-clamp recordings in layer V/VI rat pyramidal neurons from PFC slices. After blockade of all major amino acid receptors ( V hold = −65 mV) brief tetanic stimulation (20 Hz) of local afferents or application of the D1 agonist [SKF81297][1] (0.2–50 μM) induced LTP-IE, as shown by a prolonged (>40 min) increase in depolarizing pulse-evoked spike firing. Pretreatment with the D1/5 antagonist [SCH23390][2] (1 μM) blocked both the tetani- and D1/5 agonist-induced LTP-IE, suggesting a D1/5 receptor-mediated mechanism. The [SKF81297][1]-induced LTP-IE was significantly attenuated by Cd2+, [Ca2+]i chelation, by inhibition of phospholipase C, protein kinase-C, and Ca2+/calmodulin kinase-II, but not by inhibition of adenylate cyclase, protein kinase-A, MAP kinase, or L-type Ca2+ channels. Thus this form of D1/5 receptor-mediated LTP-IE relied on Ca2+ influx via non-L-type Ca2+ channels, activation of PLC, intracellular Ca2+ elevation, activation of Ca2+-dependent CaMKII, and PKC to mediate modulation of voltage-dependent ion channel(s). This D1/5 receptor-mediated modulation by PKC coexists with the previously described PKA-dependent modulation of K+ and Ca2+ currents to dynamically regulate overall excitability of PFC neurons. [1]: /lookup/external-ref?link_type=GENPEPT&access_num=SKF81297&atom=%2Fjn%2F97%2F3%2F2448.atom [2]: /lookup/external-ref?link_type=GENPEPT&access_num=SCH23390&atom=%2Fjn%2F97%2F3%2F2448.atom