Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 32, Pages 13118-13123Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1201011109
Keywords
fast-spiking interneuron; attention-deficit/hyperactivity disorder; cognitive enhancers; excitatory/inhibitory balance
Categories
Funding
- Karolinska Institute doctoral fellowship
- Karolinska Institute/National Institutes of Health Graduate Partnerships Program
- grants from the Swedish Research Council (Vetenskapsradet)
- Swedish Brain Fund (Hjarnfonden)
- Strategic Program in Neurosciences at Karolinska Institute (StratNeuro)
- Swedish Medical Association (Svenska Lakaresallskapet)
- Karolinska Institute
- NICHD Intramural Research Program
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The neuregulin/ErbB signaling network is genetically associated with schizophrenia and modulates hippocampal gamma 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 gamma 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 gamma 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 gamma 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 gamma oscillation power. This unique link between D4R and ErbB4 signaling on gamma 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 gamma oscillations, and suggest potential benefits of D4R modulators for targeting cognitive deficits.
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