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Sci Rep ; 7(1): 15571, 2017 Nov 14.
Article in English | MEDLINE | ID: mdl-29138490

ABSTRACT

Long-term potentiation (LTP) is the persistent increase in the strength of the synapses. However, the neural networks would become saturated if there is only synaptic strenghthening. Synaptic weakening could be facilitated by active processes like long-term depression (LTD). Molecular mechanisms that facilitate the weakening of synapses and thereby stabilize the synapses are also important in learning and memory. Here we show that blockade of dopaminergic D4 receptors (D4R) promoted the formation of late-LTP and transformed early-LTP into late-LTP. This effect was dependent on protein synthesis, activation of NMDA-receptors and CaMKII. We also show that GABAA-receptor mediated mechanisms are involved in the enhancement of late-LTP. We could show that short-term plasticity and baseline synaptic transmission were unaffected by D4R inhibition. On the other hand, antagonizing D4R prevented both early and late forms of LTD, showing that activation of D4Rs triggered a dual function. Synaptic tagging experiments on LTD showed that D4Rs act as plasticity related proteins rather than the setting of synaptic tags. D4R activation by PD 168077 induced a slow-onset depression that was protein synthesis, NMDAR and CaMKII dependent. The D4 receptors, thus exert a bidirectional modulation of CA1 pyramidal neurons by restricting synaptic strengthening and facilitating synaptic weakening.


Subject(s)
CA1 Region, Hippocampal/drug effects , Neuronal Plasticity/physiology , Receptors, Dopamine D4/genetics , Synapses/genetics , Animals , Benzamides/administration & dosage , CA1 Region, Hippocampal/physiopathology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/physiology , Gene Expression Regulation/drug effects , Hippocampus/drug effects , Hippocampus/physiopathology , Humans , Long-Term Potentiation/physiology , Long-Term Synaptic Depression/drug effects , Membrane Glycoproteins/genetics , Nerve Net/drug effects , Nerve Net/physiopathology , Neuronal Plasticity/drug effects , Piperazines/administration & dosage , Protein Biosynthesis/drug effects , Rats , Receptors, Dopamine D4/antagonists & inhibitors , Synapses/drug effects , Synaptic Transmission/drug effects , Synaptic Transmission/genetics
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