title: Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors.
abstract: The neuregulin/ErbB signaling network is genetically associated with schizophrenia and modulates hippocampal γ oscillations--a type of neuronal network activity important for higher brain processes and altered in psychiatric disorders. Because neuregulin-1 (NRG-1) dramatically increases extracellular dopamine levels in the hippocampus, we investigated the relationship between NRG/ErbB and dopamine signaling in hippocampal γ oscillations. Using agonists for different D1- and D2-type dopamine receptors, we found that the D4 receptor (D4R) agonist PD168077, but not D1/D5 and D2/D3 agonists, increases γ oscillation power, and its effect is blocked by the highly specific D4R antagonist L-745,870. Using double in situ hybridization and immunofluorescence histochemistry, we show that hippocampal D4R mRNA and protein are more highly expressed in GAD67-positive GABAergic interneurons, many of which express the NRG-1 receptor ErbB4. Importantly, D4 and ErbB4 receptors are coexpressed in parvalbumin-positive basket cells that are critical for γ oscillations. Last, we report that D4R activation is essential for the effects of NRG-1 on network activity because L-745,870 and the atypical antipsychotic clozapine dramatically reduce the NRG-1-induced increase in γ oscillation power. This unique link between D4R and ErbB4 signaling on γ oscillation power, and their coexpression in parvalbumin-expressing interneurons, suggests a cellular mechanism that may be compromised in different psychiatric disorders affecting cognitive control. These findings are important given the association of a DRD4 polymorphism with alterations in attention, working memory, and γ oscillations, and suggest potential benefits of D4R modulators for targeting cognitive deficits.
authors: Neuronal Oscillations Laboratory, KI-Alzheimer Disease Research Center, Department of Neurobiology, Care Sciences and Society,  Karolinska Institute, 14186 Stockholm,  Sweden.
authors: Richard H
authors: RH
authors: Andersson
authors: April
authors: A
authors: Johnston
authors: Paul A
authors: PA
authors: Herman
authors: Ursula H
authors: UH
authors: Winzer-Serhan
authors: Irina
authors: I
authors: Karavanova
authors: Detlef
authors: D
authors: Vullhorst
authors: André
authors: A
authors: Fisahn
authors: Andres
authors: A
authors: Buonanno
mesh_terms: D000818:Animals; D058256:Brain Waves / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005583:Fourier Analysis; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007395:Interneurons / Q000378:metabolism; D020880:Neuregulins / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D020880:Neuregulins; D011725:Pyridines; D011758:Pyrroles; D050638:Receptors, Dopamine D4; D004298:Dopamine