Dopamine D4 Receptor Activation Increases Hippocampal Gamma Oscillations by Enhancing Synchronization of Fast-Spiking Interneurons

Abstract

BackgroundGamma 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 FindingsTo 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 oscillations after application of PD168077. Fast-spiking, but not non-fast spiking, interneurons, increase their action potential phase-coupling and coherence with regard to ongoing gamma oscillations in response to D4R activation. Among several possible mechanisms we found that the NMDA receptor antagonist AP5 also blocks the D4R mediated increase in gamma oscillation power.Conclusions/SignificanceWe conclude that D4R activation affects fast-spiking interneuron synchronization and thereby increases gamma power by an NMDA receptor-dependent mechanism. This suggests that converging deficits on fast-spiking interneurons may lead to decreased network function and thus aberrant gamma oscillations and cognitive decline in schizophrenia.

Amyloid-β-Induced Action Potential Desynchronization and Degradation of Hippocampal Gamma Oscillations Is Prevented by Interference with Peptide Conformation Change and Aggregation

“…We have found that a domain from Araneus ventricosus minor ampullate spidroin (Chen et al, 2012) forms typical amyloid-like fibrils, as judged by Thioflavin-T fluorescence, electron microscopy, and Congo red staining. Such fibrils were made by incubating 10 M of A. ventricosus MiSp domain under quiescent conditions at 25°C in 50 mM sodium acetate buffer, pH 5.2, for 8 h. The fibrils were diluted to 50 nM and studied as described for A␤ fibrils.…”

“…Desynchronization of AP firing in various cell types is a possible cause for degradation of network rhythms (Andersson et al, 2010(Andersson et al, , 2012Leão et al, 2012). Recording pyramidal cell (PC) AP in area CA3 in cell-attached patch-clamp mode and concomitant extracellular gamma oscillations (100 nM KA) we found that application of A␤ (1 M) led to a steady degradation of gamma oscillation power (to 80 Ϯ 2.3% of control, n ϭ 26, p Ͻ 0.0001; Fig.…”

Oscillations and Neuronal Dynamics in Schizophrenia: The Search for Basic Symptoms and Translational Opportunities

“…In addition to inhibitory and excitatory neurotransmission, there is also evidence for the potential contribution of monoamines, such as DA, to the modulation of high-frequency oscillations [44][45][46] [47]. However, further research is required to systematically address this relationship.…”

Reduced Gamma Oscillations in a Mouse Model of Intellectual Disability: A Role for Impaired Repetitive Neurotransmission?

“…Gamma and other cortical oscillations associated with cognition depend on the repetitive activity of inhibitory neurons and intermittent activity in excitatory neurons, and so the ability of inhibitory synapses to operate at these frequencies is critical [6], [18].…”