Elsevier

Neuroscience

Volume 475, 1 November 2021, Pages 83-92
Neuroscience

Research Article
The Cellular Mechanisms of Dopamine Modulation on the Neuronal Network Oscillations in the CA3 Area of Rat Hippocampal Slices

https://doi.org/10.1016/j.neuroscience.2021.09.005Get rights and content

Highlights

  • Dopamine (DA) increased kainate-induced γ oscillations in the CA3 area of rat hippocampal slices.

  • DA-mediated increase in γ power is associated with dopamine receptor (DR) 1 and 2 activation.

  • Receptor tyrosine kinase (RTK) and ERK are the main intracellular kinases that mediate DA enhancement of γ.

  • DA-mediated enhancement of γ oscillation is involved in the activation of DR1/2-RTK-ERK signaling pathway.

Abstract

Network oscillations at γ frequency band (30–80 Hz), generated by the interaction between inhibitory interneurons and excitatory neurons, have been proposed to be associated with higher brain functions such as learning and memory. Dopamine (DA), one of the major CNS transmitters, modulates hippocampal γ oscillations but the intracellular mechanisms involved remain elusive. In this study, we recorded kainate-induced γ oscillations in the CA3 area of rat hippocampal slices, and found that DA strongly enhanced γ power, which was largely blocked by dopamine receptor 1 (DR1) antagonist SCH23390, receptor tyrosine kinase (RTK) inhibitor UNC569 and ERK inhibitor U0126, partially blocked by D2/3R antagonist raclopride, PKA inhibitor H89 and PI3K inhibitor wortmannin, but not affected by AKT inhibitor TCBN or NMDAR antagonist D-AP5. Our results indicate that DA-mediated γ enhancement is involved in the activation of signaling pathway of DR1/2-RTK-ERK. Our data demonstrate a strong, rapid modulation of DA on hippocampal γ oscillations and provide a new insight into cellular mechanisms of DA-mediated γ oscillations.

Introduction

Gamma (γ) oscillation is a synchronous neural activity at a frequency band of 30–80 Hz, which promotes the information integration and exchange within local network and between different brain regions. Dopamine (DA), a main neurotransmitter of catecholamine in the brain, regulates a variety of brain functions such as reward, motivation, and learning and memory via activating dopamine receptors (DRs). DRs, one member of superfamily of G protein-coupled receptors (Wise, 2004), are divided into D1-like receptors (DR1 and DR5) and D2-like receptors (DR2, DR3 and DR4) (Trantham-Davidson et al., 2004, Paine et al., 2009, Buonanno, 2010, Wei et al., 2015). DR1 agonists activate the classical signal pathway of adenylyl cyclase (AC)-cAMP-protein kinase A (PKA) (Undieh, 2010), whereas DR2 agonists decrease it.

Receptor tyrosine kinases (RTK) are transmembrane proteins with intrinsic kinase activity (Schlessinger, 2014), function as an entry point for many extracellular cues and play a critical role in recruiting the intracellular signaling cascades. Essential for most RTK-mediated signaling molecules is the activation of extracellular related signal kinase (ERK) (McKay and Morrison, 2007). Cross talking between DRs and RTK signaling pathways leads to ERK/MAP kinase phosphorylation (Belcheva and Coscia, 2002). ERK phosphorylation is known to be involved in DA-mediated GluA1 membrane insertion (Song et al., 2013) and hippocampus-related spatial learning (Ogoshi and Weiss, 2003). In addition to ERK/MAP kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-Akt signaling is another downstream signaling pathway mediated by RTK (Manning and Toker, 2017). Interestingly, both DR1 and DR2 agonists cause the activation of RTK-PI3K-Akt signaling pathway (Beaulieu et al., 2011).

Pharmacologically induced γ oscillations in vitro have been proven to be a powerful model to study cellular mechanisms of network oscillations. The muscarinic acetylcholine receptor agonist carbachol (CCh) and kainate receptor agonist kainate (KA) have been used to induce hippocampal γ oscillations. Earlier study has showed that DA depresses carbachol-induced hippocampal γ oscillations via DR1 activation (Weiss et al., 2003), whereas DA increases KA-induced γ oscillations in hippocampal slices in the presence of DR1 antagonist (Andersson et al., 2012a, Andersson et al., 2012b, Furth et al., 2013). Recently we have found DA increases CCh-induced γ oscillations in mouse hippocampal slices (Wang et al., 2019), these inconsistent results warrant further study to clarify the role of DA on γ oscillation and the mechanisms involved. Previous study indicates that nicotine-mediated enhancement of γ oscillations is involved in activation of multiple kinases (Wang et al., 2017). Whether aforementioned signaling molecules are implicated in DA-mediated γ oscillation is unclear. In this study, we demonstrate that DA significantly increases the KA-induced γ oscillations by activating mainly the RTK-ERK signaling pathway and partially by PKA and PI3K.

Section snippets

Animals

All animal use procedures were approved by the Ethics Committees at Xinxiang Medical University for the Care and Use of Laboratory Animals, and all efforts were made to minimize animal suffering and reduce the number of animals used. A total of 76 brain slices from 36 individual rats were used in this study. Electrophysiological studies were performed on hippocampal slices prepared from Sprague Dawley rats (male, 4–5 week-old). For electrophysiology, the animals were anaesthetized by

The effect of DA on kainate-induced γ oscillations

To investigate the effect of DA on the γ oscillation-generating network in hippocampal CA3, γ oscillations were induced by perfusing hippocampal slices with 200 nM KA in vitro (Cunningham et al., 2003). After usually 1 to 2 hr application of KA, γ oscillations reached a steady state (maintaining a power level for at least 20 min) with an median power value of 3230 (1509, 9441) µV2 (n = 18 slices from 10 rats, measured at 15th-20th min of the steady state) and a peak frequency of 29 ± 0.8 Hz

Discussion

In this study, we demonstrated that DA strongly and rapidly enhanced KA-induced γ oscillations in the rat hippocampal slices, which is involved in activation of multiple kinases, mainly RTK-ERK signaling molecules, and PKA and PI3K in less content (Fig. 6).

By using a model of carbachol (CCh)-induced γ oscillations in rat hippocampus, Weiss et al. showed DA suppressed CCh-induced γ oscillations (Weiss et al., 2003, Mayne et al., 2013), which is different from DA enhancement of KA-induced γ

Author contributions

XEX performed the experiments, analyzed the data and wrote the paper; MCL and ZYS performed the experiments; YZ analyzed the data; CL designed the experiments, analyzed the data, wrote and revised the paper.

Declarations of interest

None.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (NSFC, grant numbers: 81771517, Xinxiang Medical University Taihang Scholar Start Fund).

References (42)

  • U. Schmidt et al.

    Differentiative effects of dopamine on striatal neurons involve stimulation of the cAMP/PKA pathway

    Mol Cell Neurosci

    (1998)
  • A.S. Undieh

    Pharmacology of signaling induced by dopamine D(1)-like receptor activation

    Pharmacol Therap

    (2010)
  • H.Y. Wang et al.

    Study on fluorescence property of dopamine and determination of dopamine by fluorimetry

    Talanta

    (2002)
  • J. Wang et al.

    Multiple kinases involved in the nicotinic modulation of gamma oscillations in the rat hippocampal CA3 area

    Front Cell Neurosci

    (2017)
  • L. Wei et al.

    Dopamine receptor DR2 expression in B cells is negatively correlated with disease activity in rheumatoid arthritis patients

    Immunobiology

    (2015)
  • R. Andersson et al.

    Dopamine D4 receptor activation increases hippocampal gamma oscillations by enhancing synchronization of fast-spiking interneurons

    Plos One

    (2012)
  • R.H. Andersson et al.

    Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

    Proc Natl Acad Sci U S A

    (2012)
  • J.M. Beaulieu et al.

    Beyond cAMP: The regulation of Akt and GSK3 by dopamine receptors

    Front Mol Neurosci

    (2011)
  • M.M. Belcheva et al.

    Diversity of G protein-coupled receptor signaling pathways to ERK/MAP kinase

    Neurosignals

    (2002)
  • L.F. Burbulla et al.

    Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease

    Science

    (2017)
  • C. Cheng et al.

    PI3K signaling in glioma–animal models and therapeutic challenges

    Brain Pathol

    (2010)
  • View full text