dopamine d4 receptor activation increases hippocampal gamma oscillations by enhancing synchronization of fast-spiking interneurons多巴胺d4受体激活增加海马伽马振荡通过增强同步fast-spiking中间神经元.pdfVIP

Dopamine D4 Receptor Activation Increases Hippocampal Gamma Oscillations by Enhancing Synchronization of Fast-Spiking Interneurons ´ Richard Andersson, April Johnston, Andre Fisahn* Neuronal Oscillations Laboratory, KI-Alzheimer Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden Abstract Background: Gamma oscillations are electric activity patterns of the mammalian brain hypothesized to serve attention, sensory perception, working memory and memory encoding. They are disrupted or altered in schizophrenic patients with associated cognitive deficits, which persist in spite of treatment with antipsychotics. Because cognitive symptoms are a core feature of schizophrenia it is relevant to explore signaling pathways that potentially regulate gamma oscillations. Dopamine has been reported to decrease gamma oscillation power via D1-like receptors. Based on the expression pattern of D4 receptors (D4R) in hippocampus, and pharmacological effects of D4R ligands in animals, we hypothesize that they are in a position to regulate gamma oscillations as well. Methodology/Principal Findings: To address this hypothesis we use rat hippocampal slices and kainate-induced gamma oscillations. Local field potential recordings as well as intracellular recordings of pyramidal cells, fast-spiking and non-fast- spiking interneurons were carried out. We show that D4R activation with the selective ligand PD168077 increases gamma oscillation power, which can be blocked by the D4R-specific antagonist L745,870 as well as by the antipsychotic drug Clozapine. Pyramidal cells did not exhibit changes in excitatory or inhibitory synaptic current amplitudes, but inhibitory currents became more coherent with the oscill