Journal Article

Bidirectional modulation of hippocampal synaptic plasticity by Dopaminergic D4-receptors in the CA1 area of hippocampus

Tay, Sabrina Jia Ning, Navakkode, Sheeja, Soong, Tuck Wah, Chew, Katherine C. M., Lin, Qingshu, Behnisch, Thomas

2017

Overview

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 GABA A -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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/1595 / 631/443/376 / Animals / Benzamides - administration & dosage / CA1 Region, Hippocampal - drug effects / CA1 Region, Hippocampal - physiopathology / Ca2+/calmodulin-dependent protein kinase II / Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics / Dopamine D4 receptors / Dopaminergic Neurons - drug effects / Dopaminergic Neurons - physiology / Gene Expression Regulation - drug effects / Glutamic acid receptors (ionotropic) / Hippocampal plasticity / Hippocampus / Hippocampus - drug effects / Hippocampus - physiopathology / Humanities and Social Sciences / Humans / Learning / Long-term depression / Long-term potentiation / Long-Term Potentiation - physiology / Long-Term Synaptic Depression - drug effects / Membrane Glycoproteins - genetics / Memory / Molecular modelling / multidisciplinary / N-Methyl-D-aspartic acid receptors / Nerve Net - drug effects / Nerve Net - physiopathology / Neural networks / Neuromodulation / Neuronal Plasticity - drug effects / Neuronal Plasticity - physiology / Piperazines - administration & dosage / Plasticity / Protein biosynthesis / Protein Biosynthesis - drug effects / Protein synthesis / Pyramidal cells / Rats / Receptors, Dopamine D4 - antagonists & inhibitors / Receptors, Dopamine D4 - genetics / Science / Science (multidisciplinary) / Synapses / Synapses - drug effects / Synapses - genetics / Synaptic depression / Synaptic plasticity / Synaptic strength / Synaptic transmission / Synaptic Transmission - drug effects / Synaptic Transmission - genetics / γ-Aminobutyric acid A receptors