ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
Cyclin-dependent kinase 5 in the ventral tegmental area regulates depression-related behaviors.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 52 citations in OpenAlex.
- CDK5-Induced HCN2 Channel Dysfunction in the Prelimbic Cortex Drives Allodynia and Anxiety-Like Behaviors in Neuropathic Pain.Neuroscience bulletin · 2025Article
- Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.Signal transduction and targeted therapy · 2025Review
- CDK5: Insights into its roles in diseases.Molecular biology reports · 2025Review
- Optogenetics and chemogenetics: key tools for modulating neural circuits in rodent models of depression.Frontiers in neural circuits · 2025Review
- Valproic Acid-Induced Anxiety and Depression Behaviors are Ameliorated in p39 Cdk5 Activator-Deficient Mice.Neurochemical research · 2022Article
- Revisiting the antidepressant-like effects of desipramine in male and female adult rats: sex disparities in neurochemical correlates.Pharmacological reports : PR · 2022Article
- CB2 Agonist GW842166x Protected against 6-OHDA-Induced Anxiogenic- and Depressive-Related Behaviors in Mice.Biomedicines · 2022Article
- Chemogenetics as a neuromodulatory approach to treating neuropsychiatric diseases and disorders.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Review
- Update on GPCR-based targets for the development of novel antidepressants.Molecular psychiatry · 2022Review
- Neuronal Nitric Oxide Synthase in Nucleus Accumbens Specifically Mediates Susceptibility to Social Defeat Stress through Cyclin-Dependent Kinase 5.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- A Study to Decipher the Potential Effects of Butylphthalide against Central Nervous System Diseases Based on Network Pharmacology and Molecular Docking Integration Strategy.Evidence-based complementary and alternative medicine : eCAM · 2021Article
- Behavioral effects of SGK1 knockout in VTA and dopamine neurons.Scientific reports · 2020Article
- In vivo locus-specific editing of the neuroepigenome.Nature reviews. Neuroscience · 2020Review
- The molecular and cellular mechanisms of depression: a focus on reward circuitry.Molecular psychiatry · 2019Review
- The signaling proteins GPR158 and RGS7 modulate excitability of L2/3 pyramidal neurons and control A-type potassium channel in the prelimbic cortex.The Journal of biological chemistry · 2019Article
- Rostrocaudal subregions of the ventral tegmental area are differentially impacted by chronic stress.Psychopharmacology · 2019Article
- Wiring the depressed brain: optogenetic and chemogenetic circuit interrogation in animal models of depression.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2019Review
- Cross-species systems analysis identifies gene networks differentially altered by sleep loss and depression.Science advances · 2018Article
- CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells.Cell reports · 2018Article
- VTA mTOR Signaling Regulates Dopamine Dynamics, Cocaine-Induced Synaptic Alterations, and Reward.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2018Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Dopamine neurons in the ventral tegmental area (VTA) govern reward and motivation and dysregulated dopaminergic transmission may account for anhedonia and other symptoms of depression. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that regulates a broad range of brain functions through phosphorylation of a myriad of substrates, including tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis. We investigated whether and how Cdk5 activity in VTA dopamine neurons regulated depression-related behaviors in mice. Using the Cre/LoxP system to selectively delete Cdk5 in the VTA or in midbrain dopamine neurons in Cdk5(loxP/loxP) mice, we showed that Cdk5 loss of function in the VTA induced anxiety- and depressive-like behaviors that were associated with decreases in TH phosphorylation at Ser31 and Ser40 in the VTA and dopamine release in its target region, the nucleus accumbens. The decreased phosphorylation of TH at Ser31 was a direct effect of Cdk5 deletion, whereas decreased phosphorylation of TH at Ser40 was likely caused by impaired cAMP/protein kinase A (PKA) signaling, because Cdk5 deletion decreased cAMP and phosphorylated cAMP response element-binding protein (p-CREB) levels in the VTA. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology, we showed that selectively increasing cAMP levels in VTA dopamine neurons increased phosphorylation of TH at Ser40 and CREB at Ser133 and reversed behavioral deficits induced by Cdk5 deletion. The results suggest that Cdk5 in the VTA regulates cAMP/PKA signaling, dopaminergic neurotransmission, and depression-related behaviors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.