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Nicotine exposure of the unborn: effects on postnatal maturation of excitatory synaptic transmission in the cortico-limbic system.

Applicant Bellone Camilla
Number 131736
Funding scheme Ambizione
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.01.2011 - 31.12.2013
Approved amount 582'200.00
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Keywords (7)

Synaptic transmission; Glutamate receptors; Prenatal nicotine exposure; Dopamine; Midbrain system; Drugs of abuse; Development

Lay Summary (English)

Lead
Lay summary
One out of five women abuse drugs while pregnant (NIDA Notes 1995). Although this obviously affects the health of the mother, it may also indirectly compromise the well being of the offspring. In addition, drugs of abuse can have direct effects on the fetus. Both legal drugs such as nicotine and illicit ones such as cocaine can produce severe deficiencies in brain development.

We hypothesize that both nicotine and cocaine exposure to the fetus delays the postnatal maturation of glutamatergic tranmission onto dopamine neurons (DA) of the ventral tegmental area in mice. These alterations may have an impact directly on properties of DA neurons and secondarily, on target regions of dopaminergic system, such as the prefrontal cortex (PFC), altogether leading to neurobehavioral changes in the offspring.

The completion of this project will allow us to understand the rules governing maturation of synaptic transmission in both the VTA as well as the dopamine-ascending pathway that arises in the midbrain in the situation of excessive dopamine levels during development. We will identify changes in brain reward circuitry that may contribute to the vulnerability of adults who engage in drug seeking or drug consuming behavior after exposure to the same drug pre-natally. These changes could also have a potential impact on global child intellectual function and play an important role in learning dysfunction such as Attention Deficit Hyperactivity Disorder (ADHD).
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors.
Yuan Tifei, Mameli Manuel, O' Connor Eoin, Dey Partha, Verpelli Chiara, Sala Carlo, Perez-Otano Isabel, Lüscher Christian, Bellone Camilla (2013), Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors., in Neuron, 80(4), 1025.
Glutamatergic receptors at developing synapses: the role of GluN3A-containing NMDA receptors and GluA2-lacking AMPA receptors.
Yuan Tifei, Bellone Camilla (2013), Glutamatergic receptors at developing synapses: the role of GluN3A-containing NMDA receptors and GluA2-lacking AMPA receptors., in European Journal Pharmacology, 107.
NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.
Paoletti Pierre, Bellone Camilla, Zhou Qiang (2013), NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease., in Nat. Rev. Neurosci., 383.
Drug-evoked plasticity: do addictive drugs reopen a critical period of postnatal synaptic development?
Bellone Camilla, Lüscher Christian (2012), Drug-evoked plasticity: do addictive drugs reopen a critical period of postnatal synaptic development?, in Front Mol Neurosci, 2012;5:75.
mGluR-Dependent Synaptic Plasticity in Drug-Seeking.
Camilla Bellone, Manuel Mameli (2012), mGluR-Dependent Synaptic Plasticity in Drug-Seeking., in Front Pharmacol., 2012;3:159.
In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA.
Bellone Camilla, Mameli Manuel, Lüscher Christian (2011), In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA., in Nature neuroscience, 14(11), 1439-46.
In vivo reprogramming of circuit connectivity in postmitotic neocortical neurons.
De la Rossa andres, Bellone Camilla, Golding Bruno, Vitali Ilaria, Moss Jonathan, Toni Nicolas, Lüscher Christian, Jabaudon Denis, In vivo reprogramming of circuit connectivity in postmitotic neocortical neurons., in n vivo reprogramming of circuit connectivity in postmitotic neocortical neurons, on line-doi:10.103.
Retinal Input Directs the Recruitment of Inhibitory Interneurons Into Thalamic Visual Circuits.
Golding Bruno, Pouchelon Gabrielle, Bellone Camilla, Murthy Sahana, DiNardo Ariel, Govindan Subashoka, Luscher Christian, Shimogori Tomomi, Dayer Alexandre, Jabaudon Denis, Retinal Input Directs the Recruitment of Inhibitory Interneurons Into Thalamic Visual Circuits., in Neuron, Accepted.
Synaptic Basis of Social Dysfunction: A focus on Postsynaptic Proteins Linking Group-I mGluRs with AMPARs and NMDARs
O' Connor Eoin, Bariselli Sebastiano, Bellone Camilla, Synaptic Basis of Social Dysfunction: A focus on Postsynaptic Proteins Linking Group-I mGluRs with AMPARs and NMDARs, in EJN, Accepted.

Collaboration

Group / person Country
Types of collaboration
National Research Center Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
CIMA Spain (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
GRC, Excitatory synapses Talk given at a conference 09.06.2013 Le Diableret, Switzerland Bellone Camilla; O'Connor Eoin Cornelius;
FENS Poster 12.07.2012 Barcelona, Spain Bellone Camilla;
CINP Talk given at a conference 03.06.2012 Stockholm, Sweden Bellone Camilla;
Biennial Meeting of ISN-ESN, Talk given at a conference 28.08.2011 Athens, Greece, Greece Bellone Camilla;
44th Annual Winter Conference on Brian Research, Talk given at a conference 22.01.2011 Keystone, Colorado, United States of America Bellone Camilla;


Self-organised

Title Date Place
Synaptic Basis of Diseases 11.07.2012 Geneve, Switzerland

Awards

Title Year
Pfizer Prize for research 2014 2014
Fondation Gertrude Von Meissner 2012

Abstract

Background: Nicotine from tobacco smoking is one of the most highly addictive substances and has a major social and health consequence. However tobacco exposure is not only a health concern for adults; it has been shown to exert deleterious effects on the health of the fetus, newborn and adolescent as well. Tobacco in fact is the most commonly used substance during pregnancy (up to 25% pregnant women smoke) and direct effects of nicotine predict neurobehavioral deficits in the offspring, which may have long-lasting effects on brain function and cognition. Animal models that mimic nicotine levels of pregnant women produce neurobehavioral effect in the offspring including changes in locomotors activity, reward system and cognition. Nicotine in fact crosses the placenta and interacts with nicotine acetylcholine receptors (nAChRs). This interaction physiologically regulates the catecholamine function in the central nervous system (CNS), therefore it is not surprising that noradrenergic and dopaminergic synaptic transmissions are affected adversely by in utero nicotinic exposure.Hypothesis: We hypothesize that fetal nicotine exposure delays the postnatal maturation of glutamatergic transmission onto dopamine neurons (DA) of the ventral tegmental area (VTA) in mice. These alterations may have an impact directly on proprieties of DA neurons and secondarily on target regions of dopaminergic system such as the prefrontal cortex (PFC), leading to neurobehavioral effects in the offspring. Aims: To test these hypotheses we propose the following specific aims:1.To determine the effects of nicotine fetal exposure on excitatory postsynaptic transmission onto DA neurons of the VTA during postnatal maturation, and the effects of nicotine on spine morphology. 2.To establish the developmental pattern of a4ß2 heteromeric channels and a7 homomeric channels in neurons of the VTA.3.To identify the nicotinic receptors, which drive the effects of nicotine in utero (distinguish between a4ß2 heteromeric channels and a7 homomeric channels).4.To elucidate the effects of prenatal nicotine exposure on DA neuron excitability and on the modulation of baseline neuronal communication within the cortico-limbic network.Research design: To achieve these aims we will expose pregnant mice to nicotine in utero and will use advance electrophysiological and pharmacological approach in acute slices of VTA and PFC of offspring in combination with in vivo electrophysiological recordings. We will also take advance of modern transfection technology and imaging of single neurons (2-photon line scanning microscopy, 2PLSM) in order to successfully address the questions raised here.Expected value: A successful completion of the present proposal may unravel cellular mechanisms underlying the pathological changes induced by nicotine in utero exposure.
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