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J Neurophysiol 97: 2448-2464, 2007. First published January 17, 2007; doi:10.1152/jn.00317.2006
0022-3077/07 $8.00

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

¹National Standard Lab of Pharmacology for Chinese Materia Medica, Research Center of Acupuncture and Pharmacology, Nanjing University of Traditional Chinese Medicine, Nanjing, China; ²Arizona Research Laboratories, Division of Neural Systems, Memory, and Aging, University of Arizona, Tucson, Arizona; ³Department of Psychiatry and Brain Research Centre, University of British Columbia, Vancouver, Canada; and ⁴Neuroscience Discovery, Eli Lilly and Company, Indianapolis, Indiana

Submitted 24 March 2006; accepted in final form 4 January 2006

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 (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 (1 µM) blocked both the tetani- and D1/5 agonist-induced LTP-IE, suggesting a D1/5 receptor-mediated mechanism. The SKF81297-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.

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