Dopamine D1 and D5 Receptors Modulate Spike Timing-Dependent Plasticity at Medial Perforant Path to Dentate Granule Cell Synapses

Although evidence suggests that DA modulates hippocampal function, the mechanisms underlying that dopaminergic modulation are largely unknown. Using perforated-patch electrophysiological techniques to maintain the intracellular milieu, we investigated how the activation of D1-type DA receptors regulates spike timing-dependent plasticity (STDP) of the medial perforant path (mPP) synapse onto dentate granule cells. When D1-type receptors were inhibited, a relatively mild STDP protocol induced LTP only within a very narrow timing window between presynaptic stimulation and postsynaptic response. The stimulus protocol produced timing-dependent LTP (tLTP) only when the presynaptic stimulation was followed 30 ms later by depolarization-induced postsynaptic action potentials. That is, the time between presynaptic stimulation and postsynaptic response was 30 ms (Delta t = +30 ms). When D1-type receptors were activated, however, the same mild STDP protocol induced tLTP over a much broader timing window: tLTP was induced when -30 ms <=Delta t <= +30 ms. The result indicated that D1-type receptor activation enabled synaptic potentiation even when postsynaptic activity preceded presynaptic stimulation within this Delta t range. Results with null mice lacking the Kv4.2 potassium channel and with the potassium channel inhibitor, 4-aminopyridine, suggested that D1-type receptors enhanced tLTP induction by suppressing the transient I-A-type K+ current. Results obtained with antagonists and DA receptor knock-out mice indicated that endogenous activity of both D1 and D5 receptors modulated plasticity in the mPP. The DA D5 receptors appeared particularly important in regulating plasticity of the mPP onto the dentate granule cells.