title: In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA.
abstract: Maternal exposure to cocaine may perturb fetal development and affect synaptic maturation in the offspring. However, the molecular mechanism underlying such changes remains elusive. We focused on the postnatal maturation of glutamatergic transmission onto ventral tegmental area dopamine neurons in the mouse. We found that, during the first postnatal week, transmission was dominated by calcium-permeable AMPA receptors and GluN2B-containing NMDA receptors. Subsequently, mGluR1 receptors drove synaptic insertion of calcium-impermeable AMPA receptors and GluN2A-containing NMDAR. When pregnant mice were exposed to cocaine, this glutamate receptor switch was delayed in offspring as a result of a direct effect of cocaine on the fetal dopamine transporter and impaired mGluR1 function. Finally, positive modulation of mGluR1 in vivo was sufficient to rescue maturation. These data identify the molecular target through which in utero cocaine delays postnatal synaptic maturation, reveal the underlying expression mechanism of this impairment and propose a potential rescue strategy.
authors.affiliation: Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland. camilla.bellone@unige.ch
authors.forename: Camilla
authors.initials: C
authors.lastname: Bellone
authors.forename: Manuel
authors.initials: M
authors.lastname: Mameli
authors.forename: Christian
authors.initials: C
authors.lastname: Lüscher
mesh_terms: D000367:Age Factors; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D004963:Estrenes / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011073:Polyamines / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology; D011760:Pyrrolidinones / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000502:physiology; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000254:growth & development
chemical_list: D000779:Anesthetics, Local; D002121:Calcium Channel Blockers; D002614:Chelating Agents; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D004963:Estrenes; D018683:Excitatory Amino Acid Agents; D018733:Nicotinic Antagonists; D010726:Phosphodiesterase Inhibitors; D011073:Polyamines; D011760:Pyrrolidinones; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D018698:Glutamic Acid; D004533:Egtazic Acid; C034092:delta-philanthotoxin; D003042:Cocaine; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium; D004298:Dopamine