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The Amazing Brain Webinar Series: Select Topics in Neuroscience and Child
Development for the Clinician
Part IV – Nicotine and Cortical Development
Marina Picciotto, PhD
Jointly sponsored by the Association of University Centers on Disabilities, the Maternal and Child Health Bureau/Health Resources and Services Administration and Yale School of Medicine, Section of Developmental-Behavioral Pediatrics
Webinar Overview
• Webinar Recording – Visit www.aucd.org/webinars
• Q & A – Please submit your questions throughout the webinar via
the “question box” on your webinar dashboard. Questions will be answered following the presentation.
• Survey – Please complete the short survey at the end of the webinar!
Introductions
Carol Weitzman, MD, Associate Professor of Pediatrics and the Child Study Center, Yale School of Medicine
Marina Picciotto, PhD, Charles B.G. Murphy Professor, Departments of Psychiatry, Neurobiology and Pharmacology, Yale School of Medicine
Marina Picciotto, Charles B.G. Murphy Professor Depts. of Psychiatry, Neurobiology & Pharmacology Yale University School of Medicine
Developmental effects of nicotine and nicotinic acetylcholine receptors on circuits involved in passive avoidance learning
Smoking and Pregnancy
• 10.7-12.4% of US pregnant women are smokers
(Martin, J.A. et al. (2007) Natl. Vit. Stat. Rep. (56) pp1-104)
• Underestimate due to maternal self-report (England, L.J. et al. (2007) Nicotine Tob. Res. (10) pp1005-1013)
(Warland, J. et al. (2010) Midwifery Epub)
• Relapse and intermittent smoking in pregnancy
(Warland, J. et al. (2010) Midwifery Epub)
Smoking and Pregnancy • Persistent mental health effects in
exposed offspring – ADHD – Conduct Disorder – Antisocial behavior – Substance abuse – Psychotic-like symptoms / Psychiatric morbidity – Cognitive and attentional deficits
(Fried, P. et al. (1997) Neurotoxicol. Teratol. (19) pp171-183) (Button, T.M.M. et al. (2007) Early Hum. Dev. (83) pp727-732)
(Jacobsen, L.K. et al. (2007) Neuropsychopharm. (32) pp2453-2464) (Zammit, S. et al. (2009) Br. J. Psychiatr. (195) pp294-300)
(Ekblad, M. et al. (2010) Arch. Gen. Psych. (67) pp841-849)
• Does developmental tobacco exposure cause ADD?
• Which tobacco component is responsible?
• What is the underlying mechanism?
Developmental effects of smoking
nAChRs α4
β2 β2
β2 α4
α4 β2
α4 β2
α4
α4 α5
β2 β2
α4
α7 α7
α7 α7
α7
• Ligand gated ion channels • 12 potential neuronal subunits • Heteromeric vs. homomeric • Biophysical and pharmacological parameters affected by
subunit composition • Widespread and early expression in CNS
(Gotti, C. et al. (2006) TiPS (27) pp482- 491) (Gotti, C. et al. (2007) Biochem. Pharmacol. (74) pp1102-1111)
(Collins, A.C. et al. (2009) Handbook Expt. Pharmacol. (192) pp85-112)
Developmental effects of nicotine
• nAChR stimulation potentiates LTP at glutamatergic synapses in sensory cortex and thalamus
• Nicotine accelerates maturation of GABA and glutamate synapses
(Metherate; Berg)
Neurobiological studies:
Nicotinic acetylcholine receptors (nAChRs) are the primary molecular targets for nicotine
neuronal type nicotinic receptors
α 3
α 3
β 4 α 3
β 4 α 4
α 6
β 2 β 3
β 2
α 7
α 7
α 7 α 7
α 7
muscle type nicotinic receptor
α β γ
α
δ
1
1
Mouse model of developmental nicotine exposure
• Nicotine-treated drinking water • Dam drinks throughout pregnancy
• Nicotine levels vary and are low during sleep • Pups are exposed to nicotine that crosses the
placenta or is delivered through mother’s milk
Testing Time entry to dark chamber
The image part with relationship ID rId3 was not found in the file.
dark compartment
light compartment
The image part with relationship ID rId3 was not found in the file.
- Dams 200 ug/ml nicotine in drinking water - Offspring weaned on water (3 - 4 weeks), tested as adults (3 - 5 months).
Nicotine during development results in hypersensitive passive avoidance in adulthood
Tim
e to
ent
er d
ark
cham
ber (
sec)
NIC
E1 Birth P21 P90
NIC PA
King et al, J. Neuroscience, 2003
WT KO
.
training testing
120
100
80
60
40
20
0 wildtype knockout
Constitutive β2 subunit knockout results in hypersensitive passive avoidance learning
Picciotto et al, Nature, 1995
Tim
e to
ent
er d
ark
(sec
)
Testing Time entry to dark chamber
The image part with relationship ID rId6 was not found in the file.
dark light compartment
The image part with relationship ID rId6 was not found in the file.
Questions to be answered:
•Where in the brain is this happening?
•When during development are nAChRs necessary for this effect?
•Does this have relevance for human beings?
Questions to be answered:
•Where in the brain is this happening?
•When during development are nAChRs necessary for this effect?
•Does this have relevance for human beings?
Inducible region specific expression
Temporal-control of gene expression
β2 +/-
β2 -/-
β2 tr(CT)
β2 tr(VN)
β2 tr(VTA)
β2 tr(FB) (CamKII-tTA)
Region-specific β2 nAChR expression
King et al, J. Neuroscience, 2003
wildtype β2 knockout transgenic Nicotine binding
in situ hybridization
thalamus
cortex Rubidium efflux
Thalamic Relay Neuron
Sensory Input
IV
V
VI
Thalamic Reticular Neuron
Adapted from: Miyata, M. (2007) Neurosci. Res. (59) pp377-382
Reichova, I. and Sherman, S.M. (2004) J. Neurophysiol. (92) pp2185-2197
Cortico-Thalamic Circuitry
Thalamic Relay Neuron
Sensory Input
IV
V
VI
Thalamic Reticular Neuron
Adapted from: Miyata, M. (2007) Neurosci. Res. (59) pp377-382
Reichova, I. and Sherman, S.M. (2004) J. Neurophysiol. (92) pp2185-2197
Cortico-Thalamic Circuitry a7 modulated synapse
(Metherate)
Thalamic Relay Neuron
Sensory Input
IV
V
VI
Thalamic Reticular Neuron
Adapted from: Miyata, M. (2007) Neurosci. Res. (59) pp377-382
Reichova, I. and Sherman, S.M. (2004) J. Neurophysiol. (92) pp2185-2197
Cortico-Thalamic Circuitry
β2* modulated synapse?
Corticothalamic expression of β2 nAChRs rescues adult passive avoidance
King et al, J. Neurosci., 2003
Effect of developmental nicotine on PA depends on corticothalamic β2* nAChRs
mean time to enter
dark chamber
(sec)
0
50
100
150
200
250
300
Saline Nicotine Saline Nicotine KO CT Transgenics
Tim
e to
en
ter
the
dar
k ch
amb
er (
sec)
Train Test
***
Heath et al, Neuropsychopharmacology, 2010
PA
E1 Birth P21 P90
NIC NIC
Other nAChR subunits expressed by corticothalamic neurons
• α5:
α5 In-situ hybridization
Heath et al, Neuropsychopharmacology, 2010
α5 nAChR expression: functional consequences
• α5: is an accessory subunit – α4β2α5 nAChRs exhibit higher
conductance and faster inactivation (Ramirez-Latorre, J. et al. (1996) Nature (380) pp347-351)
– α4β2α5 nAChRs respond differently to intracellular Ca2+
• ↓ p(open) + open duration • ↑ inter burst interval
(Girod, R. et al. (1999) Ann. NY Acad. Sci. (868) pp578-590)
α5 nAChR expression: functional consequences
• α5 nAChR subunit KO mice: – Relatively indistinguishable from WTs – Nicotine-induced seizure resistance
(Salas, R. et al. (2003) Mol. Pharmacol. (63) pp1059-1066)
• Decreased function in corticothalamic terminal nAChRs – Thalamic synaptosomal 86Rb+ efflux
(Brown, R.W. et al. (2007) J. Neurochem. (103) pp204-215)
α5 knockout mice show partial hypersensitivity in passive avoidance
Heath et al, Neuropsychopharmacology, 2010
Corticothalamic mice show rescued α4/β2/α5 nAChRs
Heath et al, Neuropsychopharmacology, 2010
Cortico-Thalamic Circuitry
Thalamic Relay Neuron
Sensory Input
IV
V
VI
Thalamic Reticular Neuron
Adapted from: Miyata, M. (2007) Neurosci. Res. (59) pp377-382
Reichova, I. and Sherman, S.M. (2004) J. Neurophysiol. (92) pp2185-2197
α4β2α5 modulated synapse
Perinatal nicotine
Questions to be answered:
•Where in the brain is this happening?
•When during development are nAChRs necessary for this effect?
•Does this have relevance for human beings?
Temporally-controlled gene expression
King et al, J. Neurosci., 2003
β2* nAChRs in corticothalamic neurons during development rescue PA
mean time to enter
dark chamber
(sec)
King et al, J. Neurosci., 2003
The β2 nAChR transgene is expressed in corticothalamic efferents after P7
Heath et al, Neuropsychopharmacology, 2010
Mouse model of developmental nicotine exposure
• Nicotine-treated drinking water • Dam drinks throughout pregnancy
• Cross foster to naïve dam = prenatal • Keep pups with dam = pre- and
postnatal • Cross foster to nicotine dam = postnatal
Nicotine affects passive avoidance when administered only posnatally
0
40
80
120
160
200
240
280
320
Sac-Sac Sac-Nic Nic-Sac Nic-Nic
train test
nicotine Saccharin
birth weaning conception Day -19.5 Day 0 Day 21
* *
Tim
e to
ent
er d
ark
cham
ber (
sec)
PA
E1 Birth P21 P90
SAC NIC NIC SAC
Heath et al, Neuropsychopharmacology, 2010
Questions to be answered:
•Where in the brain is this happening?
•When during development are nAChRs necessary for this effect?
•Does this have relevance for human beings?
Jacobsen et al, J Neuroscience, 2007
Developmental smoke exposure alters white matter maturation in internal capsule
Myelinated Optic Nerve
What we think is happening
Corticothalamic Glutamatergic Projection neuron
Cholinergic afferent from hind brain
Somatosensory neuron
Thalamocortical relay cell
Glutamatergic projection back to cortex
ACh X
Summary
• Both perinatal nicotine exposure and β2* nACHR KO result in hypersensitive passive avoidance in adulthood
• Expression in corticothalamic efferents rescues this defect in KO mice and restores nicotine sensitivity
• nAChR signaling appears to be critical for maturation of corticothalamic glutamate synapses in mice and humans
Steve Buka J-P Changeux Al Collins Sharon Grady Cecelia Gotti Leslie Jacobsen
Current lab members
Sam Blakeman Cali Calarco Emily Einstein Giana Fote Nadia Gavrilova Shefali Jain Yonwoo Jung Yann Mineur Samantha Sheppard Seth Taylor
Past lab members involved in these studies:
Christopher Heath Postdoctoral Fellow Cambridge University Sarah King Lecturer University of Sussex
NIDA
NIMH
Michael Marks Eric Nestler Tony George Stephanie O’Malley Julie Staley Michele Zoli
Collaborators
TTURC
NARSAD
Funding
Q & A
• Ask a question! – Type your question in the “question box” on your webinar
dashboard.
– The moderator will read the question.
Thank You!
• Questions about the webinar? – Email Tory Christensen([email protected])
Please take a few minutes to complete the survey!