Research ArticleThe Cellular Mechanisms of Dopamine Modulation on the Neuronal Network Oscillations in the CA3 Area of Rat Hippocampal Slices
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)
- et al.
Suppression of transient 40-Hz auditory response by haloperidol suggests modulation of human selective attention by dopamine D2 receptors
Neurosci Lett
(2000) The neuregulin signaling pathway and schizophrenia: from genes to synapses and neural circuits
Brain Res Bull
(2010)Brain overgrowth in disorders of RTK–PI3K–AKT signaling: a mosaic of malformations
Seminars Perinatol
(2015)- et al.
Local NMDA receptor hypofunction evokes generalized effects on gamma and high-frequency oscillations and behavior
Neuroscience
(2017) - et al.
The modulation of gamma oscillations by methamphetamine in rat hippocampal slices
Front Cell Neurosci
(2019) - et al.
A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala
Neuron
(2001) - et al.
The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Abeta oligomers through Tau phosphorylation
Neuron
(2013) - et al.
AKT/PKB Signaling: Navigating the Network
Cell
(2017) - et al.
Dopamine-derived salsolinol derivatives as endogenous monoamine oxidase inhibitors: occurrence, metabolism and function in human brains
Neurotoxicology
(2004) - et al.
A cAMP-activated pathway, including PKA and PI3K, regulates neuronal differentiation
Neurochem Int
(2004)
Differentiative effects of dopamine on striatal neurons involve stimulation of the cAMP/PKA pathway
Mol Cell Neurosci
Pharmacology of signaling induced by dopamine D(1)-like receptor activation
Pharmacol Therap
Study on fluorescence property of dopamine and determination of dopamine by fluorimetry
Talanta
Multiple kinases involved in the nicotinic modulation of gamma oscillations in the rat hippocampal CA3 area
Front Cell Neurosci
Dopamine receptor DR2 expression in B cells is negatively correlated with disease activity in rheumatoid arthritis patients
Immunobiology
Dopamine D4 receptor activation increases hippocampal gamma oscillations by enhancing synchronization of fast-spiking interneurons
Plos One
Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors
Proc Natl Acad Sci U S A
Beyond cAMP: The regulation of Akt and GSK3 by dopamine receptors
Front Mol Neurosci
Diversity of G protein-coupled receptor signaling pathways to ERK/MAP kinase
Neurosignals
Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease
Science
PI3K signaling in glioma–animal models and therapeutic challenges
Brain Pathol
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