Daily alcohol intake triggers aberrant synaptic pruning leading to synapse loss and anxiety-like behavior
| Autor: | Joana F. Henriques, Renata L. Alves, Ana Magalhães, Teresa Summavielle, Teresa Canedo, Camila C. Portugal, Cátia M. Silva, João B. Relvas, Renato Socodato, Tiago Almeida, Joana Tedim-Moreira |
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| Přispěvatelé: | Instituto de Investigação e Inovação em Saúde |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Ethanol / administration & dosage Synaptic pruning Alcohol abuse Anxiety Synaptic Transmission Biochemistry Synapse Neuronal Plasticity / drug effects 0302 clinical medicine Synaptic Transmission / physiology Synapses / physiology Tumor Necrosis Factor-alpha / metabolism Cells Cultured Behavior Animal / drug effects Mice Knockout 0303 health sciences Anxiety / psychology Neuronal Plasticity Behavior Animal Microglia Synapses / drug effects medicine.anatomical_structure Neuronal Plasticity / physiology Microglia / metabolism Excitatory postsynaptic potential Binge drinking Mice Transgenic Neurotransmission Behavior Animal / physiology Proinflammatory cytokine 03 medical and health sciences medicine Animals Humans Synaptic Transmission / drug effects Molecular Biology 030304 developmental biology Ethanol Tumor Necrosis Factor-alpha business.industry Anxiety / physiopathology Central Nervous System Depressants Cell Biology Microglia / drug effects medicine.disease Mice Inbred C57BL nervous system Central Nervous System Depressants / administration & dosage Ethanol / blood Synapses Microglia / cytology business Neuroscience 030217 neurology & neurosurgery |
| Popis: | Alcohol abuse adversely affects the lives of millions of people worldwide. Deficits in synaptic transmission and in microglial function are commonly found in human alcohol abusers and in animal models of alcohol intoxication. Here, we found that a protocol simulating chronic binge drinking in male mice resulted in aberrant synaptic pruning and substantial loss of excitatory synapses in the prefrontal cortex, which resulted in increased anxiety-like behavior. Mechanistically, alcohol intake increased the engulfment capacity of microglia in a manner dependent on the kinase Src, the subsequent activation of the transcription factor NF-κB, and the consequent production of the proinflammatory cytokine TNF. Pharmacological blockade of Src activation or of TNF production in microglia, genetic ablation of Tnf, or conditional ablation of microglia attenuated aberrant synaptic pruning, thereby preventing the neuronal and behavioral effects of the alcohol. Our data suggest that aberrant pruning of excitatory synapses by microglia may disrupt synaptic transmission in response to alcohol abuse. This work was financed by FEDER -Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 -Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project POCI-01-0145-FEDER-030647 (PTDC/SAU-TOX/30647/2017) in TS lab. The projects FEDER Portugal (Norte-01-0145-FEDER-000008000008—Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); FCOMP-01-0124-FEDER-021333) and FCT (PTDC/MED-NEU/31318/2017) supported work in JBR lab. CCP and RS hold employment contracts financed by national funds through FCT – Fundação para a Ciência e a Tecnologia, I.P., in the context of the program-contract described in paragraphs 4, 5 and 6 of art. 23 of Law no. 57/2016, of August 29, as amended by Law no. 57/2017 of July 2019. TC is supported by FCT (SFRH/BD/117148/2016). RLA was supported by FCT (PD/BD/114266/2016). AM was supported by FCT (IF/00753/2014). Author contributions: RS, TS, and JBR designed the project. RS, JFH, CCP, TOA, JTM, RLA, TC, CS, and AM performed experiments. RS, TS, and JBR co-supervised the study. RS and JBR wrote the original draft. RS, CCP, TS, and JBR reviewed and edited the manuscript. TS and JBR acquired funding. |
| Databáze: | OpenAIRE |
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