title: Long-Term Treatment with Low Doses of Methamphetamine Promotes Neuronal Differentiation and Strengthens Long-Term Potentiation of Glutamatergic Synapses onto Dentate Granule Neurons.
abstract: Methamphetamine (METH) is a psychostimulant, affecting hippocampal function with disparate cognitive effects, which depends on the dose and time of administration, ranging from improvement to impairment of memory. Importantly, in the United States, METH is approved for the treatment of attention deficit hyperactivity disorder. Modifications of long-term plasticity of synapses originating from the entorhinal cortex onto dentate granule cells (DGCs) have been proposed to underlie cognitive alterations similar to those seen in METH users. However, the effects of METH on synaptic plasticity of the dentate gyrus are unknown. Here, we investigated the impact of long-term administration of METH (2 mg/kg/d) on neurogenesis and synaptic plasticity of immature and mature DGCs of juvenile mice. We used a mouse model of neurogenesis (the G42 line of GAD67-GFP), in which GFP is expressed by differentiating young DGCs. METH treatment enhanced the differentiation of GFP(+) cells, as it increased the fraction of GFP(+) cells expressing the neuronal marker NeuN, and decreased the amount of immature DGCs coexpressing doublecortin. Interestingly, METH did not change the magnitude of long-term potentiation (LTP) in more immature neurons, but facilitated LTP induction in more differentiated GFP(+) and strengthened plasticity in mature GFP(-) DGCs. The METH-induced facilitation of LTP in GFP(+) neurons was accompanied with spine enlargement. Our results reveal a specific action of long-term use of METH in the long-term plasticity of excitatory synapses onto differentiating DGCs and might have important implications toward the understanding of the synaptic basis of METH-induced cognitive alterations.
authors.affiliation: Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; Sorbonne Universités, Université Pierre et Marie Curie, Unité Mixte de Recherche (UMR) S 1127, Institut National de la Santé et de la Recherche Médicale U 1127, Centre National de la Recherche Scientifique UMR 7225, and Institut du Cerveau et de la Moelle épinière, 75013 Paris, France.
authors.forename: Sofia
authors.identifier: 0000-0002-2230-5687
authors.initials: S
authors.lastname: Baptista
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, Unité Mixte de Recherche (UMR) S 1127, Institut National de la Santé et de la Recherche Médicale U 1127, Centre National de la Recherche Scientifique UMR 7225, and Institut du Cerveau et de la Moelle épinière , 75013 Paris, France.
authors.forename: Joana
authors.identifier: 0000-0001-5550-9291
authors.initials: J
authors.lastname: Lourenço
authors.affiliation: Institute of Health Sciences-North, 4585-116 Gandra, Portugal; Department of Chemistry and Biochemistry, Faculty of Sciences, Centro de Investigação em Química da Universidade do Porto, 4169-007 Porto, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Milhazes
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Sciences, Centro de Investigação em Química da Universidade do Porto , 4169-007 Porto, Portugal.
authors.forename: Fernanda
authors.identifier: 0000-0003-1050-2402
authors.initials: F
authors.lastname: Borges
authors.affiliation: Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Ana Paula
authors.identifier: 0000-0002-7802-8690
authors.initials: AP
authors.lastname: Silva
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, Unité Mixte de Recherche (UMR) S 1127, Institut National de la Santé et de la Recherche Médicale U 1127, Centre National de la Recherche Scientifique UMR 7225, and Institut du Cerveau et de la Moelle épinière , 75013 Paris, France.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bacci
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D018891:Dentate Gyrus / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology / Q000502:physiology; D000089622:Doublecortin Domain Proteins; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008839:Microelectrodes; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D000697:Central Nervous System Stimulants; D004268:DNA-Binding Proteins; D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009479:Neuropeptides; D009687:Nuclear Proteins; D049452:Green Fluorescent Proteins; D008694:Methamphetamine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: ADHD; dentate gyrus; methamphetamine; neurogenesis; synaptic plasticity