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1 National Standard Lab of Pharmacology, Nanjing University of Traditional Chinese Medicine, Nanjing, China
2 Division of Neural Systems, Memory, and Aging, University of Arizona, Tucson, Arizona, United States
3 Psychiatry & Brain Res Center, Univ of British Columbia, Vancouver, Canada
4 Psychiatry, University of British Columbia, Vancouver, Canada
5 Neuroscience Discovery, Eli Lilly & Co., Indianapolis, Indiana, United States
* To whom correspondence should be addressed. E-mail: cyang{at}lilly.com.
Prefrontal Cortex (PFC) dopamine D1/5 receptors modulate long- and short-term neuronal plasticity which may contribute to cognitive functions. Synergistic to synaptic strength modulation, direct post-synaptic 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. Following blockade of all major amino acid receptors (VHOLD= -65mV) brief tetanic stimulation (20 Hz) of local afferents or application of the D1 agonist SKF81297 (0.2 to 50µM) induced LTP-IE, as shown by a prolonged (>40mins) 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. Hence, 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 via PKC co-exists with the previously described PKA-dependent modulation of K+ and Ca2+ currents to dynamically regulate overall excitability of PFC neurons.
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