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.
Highlights
Gamma oscillations are believed to be a mechanism for neuronal processing of information relating to memory, attention [1], working memory [2], sensory stimuli and perception [3], and are correlated with cognitive performance and memory load [4]
In order to examine the effects of D4 receptors (D4R) activation on gamma oscillations in the hippocampal complex, we used the in vitro model of gamma oscillations [36]
The effects of PD168077 on gamma oscillations were blocked in the presence of Clozapine (2 mM, Fig. 1C–E, kainateinduced gamma oscillations (KA): 2.446102964.87610210 V2, Clozapine: 2.416102964.846 10210 V2, PD168077: 2.526102965.91610210 V2, n = 10, Friedman test: F2,18 = 0.60, p = 0.83), which is a widely used antipsychotic drug and an antagonist on D4R [23]
Summary
Gamma oscillations (rhythmic electric activity in neuronal networks at 30–80 Hz) are believed to be a mechanism for neuronal processing of information relating to memory, attention [1], working memory [2], sensory stimuli and perception [3], and are correlated with cognitive performance and memory load [4]. Gamma oscillations are typically recorded using electroencephalography (EEG) in humans and are present in the neocortex as well as the hippocampal complex, where the layered cytoarchitecture and the synchronized neuronal activity produces rhythmic local field potential (LFP) deflections [1]. This type of oscillatory activity is reliant upon fast rhythmic synaptic inhibition of the perisomatic regions of pyramidal cells. 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. 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
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