The Epac-Phospholipase Cε Pathway Regulates Endocannabinoid Signaling and Cocaine-Induced Disinhibition of Ventral Tegmental Area Dopamine Neurons

Tong, Jia‐Qing; Liu, Xiaojie; Vickstrom, Casey R; Li, Yan; Yu, Laikang; Lu, Youming; Smrcka, Alan V.; Liu, Qing Song

doi:10.1523/jneurosci.2810-16.2017

Cited by 27 publications

(25 citation statements)

References 93 publications

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“…4 A). Epac is a direct target for cAMP and Epac2 is highly expressed in dopaminergic neurons [45] , [46] . In the present study, we found that treatment of cells with 500 μM MPP + for 4 h decreased the expression of Epac2 to 38% compared to the control group (P < 0.001).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

Zhong

Huang

et al. 2018

Redox Biology

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Phosphodiesterase 4 (PDE4) is a promising target for the treatment of Parkinson's disease (PD). However, the underlying mechanism has not yet been well elucidated. Additionally, most of current PDE4 inhibitors produce severe nausea and vomiting response in patients, which limit their clinical application. FCPR16 is a novel PDE4 inhibitor with little emetic potential. In the present study, the neuroprotective effect and underlying mechanism of FCPR16 against cellular apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+) were examined in SH-SY5Y cells. FCPR16 (12.5–50 μM) dose-dependently reduced MPP+-induced loss of cell viability, accompanied by reductions in nuclear condensation and lactate dehydrogenase release. The level of cleaved caspase 3 and the ratio of Bax/Bcl-2 were also decreased after treatment with FCPR16 in MPP+-treated cells. Furthermore, FCPR16 (25 μM) significantly suppressed the accumulation of reactive oxygen species (ROS), prevented the decline of mitochondrial membrane potential (Δψm) and attenuated the expression of malonaldehyde level. Further studies disclosed that FCPR16 enhanced the levels of cAMP and the exchange protein directly activated by cAMP (Epac) in SH-SY5Y cells. Western blotting analysis revealed that FCPR16 increased the phosphorylation of cAMP response element-binding protein (CREB) and protein kinase B (Akt) down-regulated by MPP+ in SH-SY5Y cells. Moreover, the inhibitory effects of FCPR16 on the production of ROS and Δψm loss could be blocked by PKA inhibitor H-89 and Akt inhibitor KRX-0401. Collectively, these results suggest that FCPR16 attenuates MPP+-induced dopaminergic degeneration via lowering ROS and preventing the loss of Δψm in SH-SY5Y cells. Mechanistically, cAMP/PKA/CREB and Epac/Akt signaling pathways are involved in these processes. Our findings indicate that FCPR16 is a promising pre-clinical candidate for the treatment of PD and possibly other oxidative stress-related neuronal diseases.

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Section: Resultsmentioning

confidence: 99%

Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

Zhong

Huang

et al. 2018

Redox Biology

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“…Midbrain slices (200 μm) from male C57BL/6J mice were prepared as described previously 39 , 40 . Mice were anaesthetized by isoflurane inhalation and decapitated.…”

Section: Methodsmentioning

confidence: 99%

Resveratrol modulates cocaine-induced inhibitory synaptic plasticity in VTA dopamine neurons by inhibiting phosphodiesterases (PDEs)

Zhao

et al. 2017

Sci Rep

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Resveratrol is a natural phytoalexin synthesized by plants, including grapes. It displays a wide range of neuroprotective benefits associated with anti-aging. Recent studies have shown that resveratrol regulates dopaminergic transmission and behavioral effects of drugs of abuse. The goal of the present study is to investigate whether and how resveratrol alters basal inhibitory synaptic transmission and cocaine-induced inhibitory synaptic plasticity in dopamine neurons of the ventral tegmental area (VTA). We report that resveratrol elevated cAMP levels by itself and further potentiated a forskolininduced increase in cAMP levels in midbrain slices, consistent with reported effects of inhibition of phosphodiesterases (PDEs). Resveratrol potentiated GABA A and GABA B -mediated inhibitory postsynaptic currents (IPSCs) in VTA dopamine neurons, and these effects were mediated by a protein kinase A (PKA)-dependent enhancement of presynaptic GABA release. In addition, we found that resveratrol blocked endocannabinoid-mediated long-term synaptic depression in VTA dopamine neurons. Resveratrol pretreatments attenuated cocaine-induced conditioned place preference and blocked the cocaine-induced reduction of GABAergic inhibition in VTA dopamine neurons. Together, these results provide evidence that resveratrol modulates basal inhibitory synaptic transmission, cocaine-induced synaptic plasticity, and drug-cue associative learning.Resveratrol (3,4′,5-trihydroxy-trans-stilbene), a constituent of red wine, produces a wide range of health benefits associated with anti-aging, including protection against type 2 diabetes, obesity, cancer, heart disease, and neurodegenerative diseases 1 . Since the discovery that resveratrol mimics the life-span extending effects of calorie restriction in budding yeast 2 , this compound has attracted great interest. However, past research has focused on its role in protecting against aging-related diseases 1 . Recent studies have shown that resveratrol regulates dopaminergic transmission and behavioral effects of drugs of abuse. Acute resveratrol treatment enhances cocaine-induced increases in dopamine D 1 receptor signaling and locomotor activity in mice, presumably via mechanisms involving the inhibition of monoamine oxidases 3 . In contrast, acute resveratrol treatment is ineffective at altering methamphetamine-induced hyperactivity in mice, while repeated resveratrol treatments decrease methamphetamine-induced hyperactivity in mice and dopamine overflow from rat striatal slices 4 . There are conflicting reports regarding whether resveratrol alters cocaine-induced conditioned place preference (CPP). Resveratrol has been shown to enhance cocaine CPP by activating the NAD(+)-dependent histone deacetylase sirtuins 5 . However, another study has shown that resveratrol is ineffective in altering CPP but attenuates cocaine withdrawal-induced anxiety 6 . A recent study has identified phosphodiesterases (PDEs) as a direct target for resveratrol, and both resveratrol and the selective PDE4 inhibitor rolip...

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“…EPAC2 has been localized to both excitatory and inhibitory synapses (Woolfrey et al, 2009). Interestingly EPAC2 has been demonstrated to be important for excitatory transmission (Woolfrey et al, 2009; Yang et al, 2012) and has been shown to influence inhibitory transmission in dopamine neurons of the ventral tegmental area (Tong et al, 2017). Therefore, we were interested in examining whether loss of EPAC2 would impact excitatory and inhibitory synapses on the same neuron.…”

Section: Resultsmentioning

confidence: 99%

Loss of EPAC2 alters dendritic spine morphology and inhibitory synapse density

Jones

Sumiya

Woolfrey

et al. 2019

Molecular and Cellular Neuroscience

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EPAC2 is a guanine nucleotide exchange factor that regulates GTPase activity of the small GTPase Rap and Ras and is highly enriched at synapses. Activation of EPAC2 has been shown to induce dendritic spine shrinkage and increase spine motility, effects that are necessary for synaptic plasticity. These morphological effects are dysregulated by rare mutations of Epac2 associated with autism spectrum disorders. In addition, EPAC2 destabilizes synapses through the removal of synaptic GluA2/3-containing AMPA receptors. Previous work has shown that Epac2 knockout mice ( Epac2 −/− ) display abnormal social interactions, as well as gross disorganization of the frontal cortex and abnormal spine motility in vivo . In this study we sought to further understand the cellular consequences of knocking out Epac2 on the development of neuronal and synaptic structure and organization of cortical neurons. Using primary cortical neurons generated from Epac2 +/+ or Epac2 −/− mice, we confirm that EPAC2 is required for cAMP-dependent spine shrinkage. Neurons from Epac2 −/− mice also displayed increased synaptic expression of GluA2/3-containing AMPA receptors, as well as of the adhesion protein N-cadherin. Intriguingly, analysis of excitatory and inhibitory synaptic proteins revealed that loss of EPAC2 resulted in altered expression of vesicular GABA transporter (VGAT) but not vesicular glutamate transporter 1 (VGluT1), indicating an altered ratio of excitatory and inhibitory synapses onto neurons. Finally, examination of cortical neurons located within the anterior cingulate cortex further revealed subtle deficits in the establishment of dendritic arborization in vivo . These data provide evidence that loss of EPAC2 enhances the stability of excitatory synapses and increases the number of inhibitory inputs.

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The Epac-Phospholipase Cε Pathway Regulates Endocannabinoid Signaling and Cocaine-Induced Disinhibition of Ventral Tegmental Area Dopamine Neurons

Cited by 27 publications

References 93 publications

Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

Resveratrol modulates cocaine-induced inhibitory synaptic plasticity in VTA dopamine neurons by inhibiting phosphodiesterases (PDEs)

Loss of EPAC2 alters dendritic spine morphology and inhibitory synapse density

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