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1.
Cell Rep ; 43(8): 114529, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39046876

RESUMO

Neuronal activation is required for the formation of drug-associated memory, which is critical for the development, persistence, and relapse of drug addiction. Nevertheless, the metabolic mechanisms underlying energy production for neuronal activation remain poorly understood. In the study, a large-scale proteomics analysis of lysine crotonylation (Kcr), a type of protein posttranslational modification (PTM), reveals that cocaine promoted protein Kcr in the hippocampal dorsal dentate gyrus (dDG). We find that Kcr is predominantly discovered in a few enzymes critical for mitochondrial energy metabolism; in particular, pyruvate dehydrogenase (PDH) complex E1 subunit α (PDHA1) is crotonylated at the lysine 39 (K39) residue through P300 catalysis. Crotonylated PDHA1 promotes pyruvate metabolism by activating PDH to increase ATP production, thus providing energy for hippocampal neuronal activation and promoting cocaine-associated memory recall. Our findings identify Kcr of PDHA1 as a PTM that promotes pyruvate metabolism to enhance neuronal activity for cocaine-associated memory.


Assuntos
Cocaína , Hipocampo , Memória , Neurônios , Piruvato Desidrogenase (Lipoamida) , Animais , Cocaína/farmacologia , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Piruvato Desidrogenase (Lipoamida)/metabolismo , Memória/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Processamento de Proteína Pós-Traducional , Lisina/metabolismo , Humanos
2.
Biol Psychiatry ; 95(9): 896-908, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-37913973

RESUMO

BACKGROUND: Circular RNAs are highly enriched in the synapses of the mammalian brain and play important roles in neurological function by acting as molecular sponges of microRNAs. circAnk3 is derived from the 11th intron of the ankyrin-3 gene, Ank3, a strong genetic risk factor for neuropsychiatric disorders; however, the function of circAnk3 remains elusive. In this study, we investigated the function of circAnk3 and its downstream regulatory network for target genes in the hippocampus of mice. METHODS: The DNA sequence from which circAnk3 is generated was modified using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9) technology, and neurobehavioral tests (anxiety and depression-like behaviors, social behaviors) were performed in circAnk3+/- mice. A series of molecular and biochemical assays were used to investigate the function of circAnk3 as a microRNA sponge and its downstream regulatory network for target genes. RESULTS: circAnk3+/- mice exhibited both anxiety-like behaviors and social deficits. circAnk3 was predominantly located in the cytoplasm of neuronal cells and functioned as a miR-7080-3p sponge to regulate the expression of Iqgap1. Inhibition of miR-7080-3p or restoration of Iqgap1 in the hippocampus ameliorated the behavioral deficits of circAnk3+/- mice. Furthermore, circAnk3 deficiency decreased the expression of the NMDA receptor subunit GluN2a and impaired the structural plasticity of dendritic synapses in the hippocampus. CONCLUSIONS: Our results reveal an important role of the circAnk3/miR-7080-3p/IQGAP1 axis in maintaining the structural plasticity of hippocampal synapses. circAnk3 might offer new insights into the involvement of circular RNAs in neuropsychiatric disorders.


Assuntos
MicroRNAs , RNA Circular , Camundongos , Animais , RNA Circular/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Hipocampo/metabolismo , Encéfalo/metabolismo , Ansiedade/genética , Mamíferos/genética , Mamíferos/metabolismo
3.
ACS Chem Neurosci ; 14(9): 1585-1601, 2023 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-37043723

RESUMO

Mitochondria are highly dynamic organelles with coordinated cycles of fission and fusion occurring continuously to satisfy the energy demands in the complex architecture of neurons. How mitochondria contribute to addicted drug-induced adaptable mitochondrial networks and neuroplasticity remains largely unknown. Through liquid chromatography-mass spectrometry-based lipidomics, we first analyzed the alteration of the mitochondrial lipidome of three mouse brain areas in methamphetamine (METH)-induced locomotor activity and conditioned place preference. The results showed that METH remodeled the mitochondrial lipidome of the hippocampus, nucleus accumbens (NAc), and striatum in both models. Notably, mitochondrial hallmark lipid cardiolipin (CL) was specifically increased in the NAc in METH-induced hyperlocomotor activity, which was accompanied by an elongated giant mitochondrial morphology. Moreover, METH significantly boosted mitochondrial respiration and ATP generation as well as the copy number of mitochondrial genome DNA in the NAc. By screening the expressions of mitochondrial dynamin-related proteins, we found that repeated METH significantly upregulated the expression of long-form optic atrophy type 1 (L-OPA1) and enhanced the interaction of L-OPA1 with CL, which may promote mitochondrial fusion in the NAc. On the contrary, neuronal OPA1 depletion in the NAc not only recovered the dysregulated mitochondrial morphology and synaptic vesicle distribution induced by METH but also attenuated the psychomotor effect of METH. Collectively, upregulated CL and OPA1 cooperate to mediate METH-induced adaptation of neuronal mitochondrial dynamics in the NAc, which correlates with the psychomotor effect of METH. These findings propose a potential therapeutic approach for METH addiction by inhibiting neuronal mitochondrial fusion.


Assuntos
Metanfetamina , Camundongos , Animais , Metanfetamina/farmacologia , Núcleo Accumbens/metabolismo , Cardiolipinas/farmacologia , Dinâmica Mitocondrial , Neurônios/metabolismo , Locomoção
4.
Cell Rep ; 41(9): 111724, 2022 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-36450263

RESUMO

Studies have shown the therapeutic effects of a ketogenic diet (KD) on epilepsy, but the effect of a KD on drug reinstatement is largely unclear. This study aims to investigate whether KD consumption possesses therapeutic potential for cocaine reinstatement and the molecular mechanism. We find that a KD significantly reduces cocaine-induced reinstatement in mice, which is accompanied by a markedly elevated level of ß-hydroxybutyrate (ß-OHB), the most abundant ketone body, in the hippocampus. The underlying mechanism is that ß-OHB posttranslationally modifies CaMKII-α with ß-hydroxybutyrylation, resulting in significant inhibition of T286 autophosphorylation and downregulation of CaMKII activity. Collectively, our results reveal that ß-hydroxybutyrylation is a posttranslational modification of CaMKII-α that plays a critical role in mediating the effect of KD consumption in reducing cocaine reinstatement.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Cocaína , Animais , Camundongos , Ácido 3-Hidroxibutírico/farmacologia , Cocaína/farmacologia , Condicionamento Clássico , Hipocampo
5.
Neuropharmacology ; 213: 109076, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35500677

RESUMO

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are key regulators during the process of synaptic plasticity in major depression disorder (MDD). Synapse differentiation-induced gene 1 (SynDIG1) functions as an atypical AMPAR auxiliary subunit and regulates synaptic AMPAR content; however, the role of SynDIG1 in MDD remains elusive. In this study, we found that the SynDIG1 expression was significantly increased in the neurons of the nucleus accumbens (NAc) of male mice after chronic social defeat stress (CSDS). CSDS enhanced SynDIG1-GluA2 binding and promoted the surface expression of AMPAR subunit GluA2 in the NAc. Knockdown of SynDIG1 decreased the surface expression of GluA2 and reversed the alteration of dendrite spines in the neurons, eventually alleviating the depressive-like behaviors of the stressed mice. Moreover, intra-NAc injection of IP12, a specific peptide to disrupt the interaction of SynDIG1 with GluA2, rescued depressive-like behaviors. Collectively, SynDIG1 regulates the surface expression of GluA2 and dendritic remodeling in the NAc of male mice under CSDS, thus mediating the depressive-like behaviors.


Assuntos
Proteínas de Transporte/metabolismo , Núcleo Accumbens , Receptores de AMPA , Animais , Depressão/etiologia , Masculino , Camundongos , Núcleo Accumbens/metabolismo , Receptores de AMPA/metabolismo , Derrota Social , Sinapses/metabolismo
6.
ACS Chem Neurosci ; 12(23): 4449-4464, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34762393

RESUMO

Cefepime exhibits a broad spectrum of antimicrobial activity and thus is a widely used treatment for severe bacterial infections. Adverse effects on the central nervous system (CNS) have been reported in patients treated with cefepime. Current explanation for the adverse neurobehavioral effect of cefepime is mainly attributed to its ability to cross the blood-brain barrier and competitively bind to the GABAergic receptor; however, the underlying mechanism is largely unknown. In this study, mice were intraperitoneally administered 80 mg/kg cefepime for different periods, followed by neurobehavioral tests and a brain lipidomic analysis. LC/MS-MS-based metabolomics was used to investigate the effect of cefepime on the brain lipidomic profile and metabolic pathways. Repeated cefepime treatment time-dependently caused anxiety-like behaviors, which were accompanied by reduced locomotor activity in the open field test. Cefepime profoundly altered the lipid profile, acyl chain length, and unsaturation of fatty acids in the corpus striatum, and glycerophospholipids accounted for a large proportion of those significantly modified lipids. In addition, cefepime treatment caused obvious alteration in the lipid-enriched membrane structure, neurites, mitochondria, and synaptic vesicles of primary cultured striatal neurons; moreover, the spontaneous electrical activity of striatal neurons was significantly reduced. Collectively, cefepime reprograms glycerophospholipid metabolism in the corpus striatum, which may interfere with neuronal structure and activity, eventually leading to aberrant neurobehaviors in mice.


Assuntos
Metabolismo dos Lipídeos , Lipidômica , Animais , Cefepima , Corpo Estriado , Glicerofosfolipídeos , Humanos , Camundongos
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