The Amazing Brain Webinar Series: Select Topics in Neuroscience and Child Development for the Clinician. Part IV Nicotine and Cortical Development

Transcription

1 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

2 Webinar Recording Webinar Overview Visit 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!

3 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

4 Developmental effects of nicotine and nicotinic acetylcholine receptors on circuits involved in passive avoidance learning Marina Picciotto, Charles B.G. Murphy Professor Depts. of Psychiatry, Neurobiology & Pharmacology Yale University School of Medicine

5 Smoking and Pregnancy % 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) pp ) (Warland, J. et al. (2010) Midwifery Epub) Relapse and intermittent smoking in pregnancy (Warland, J. et al. (2010) Midwifery Epub)

6 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) pp ) (Button, T.M.M. et al. (2007) Early Hum. Dev. (83) pp ) (Jacobsen, L.K. et al. (2007) Neuropsychopharm. (32) pp ) (Zammit, S. et al. (2009) Br. J. Psychiatr. (195) pp ) (Ekblad, M. et al. (2010) Arch. Gen. Psych. (67) pp )

7 Developmental effects of smoking Does developmental tobacco exposure cause ADD? Which tobacco component is responsible? What is the underlying mechanism?

8 nachrs β2 α4 β2 β2 α4 β2 α5 α4 β2 α7 α7 α7 β2 α4 α4 α4 β2 α4 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) pp ) (Gotti, C. et al. (2007) Biochem. Pharmacol. (74) pp ) (Collins, A.C. et al. (2009) Handbook Expt. Pharmacol. (192) pp85-112)

9 Developmental effects of nicotine Neurobiological studies: nachr stimulation potentiates LTP at glutamatergic synapses in sensory cortex and thalamus Nicotine accelerates maturation of GABA and glutamate synapses (Metherate; Berg)

10 Nicotinic acetylcholine receptors (nachrs) are the primary molecular targets for nicotine α 7 α 7 α 7 α 7 α 7 1 γ α β α 1 δ muscle type nicotinic receptor α 3 β 4 α 3 α 3 β 4 α 4 α 6 β 2 β 3 neuronal type nicotinic receptors β 2

11 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

12 The image part with relationship ID rid3 was not found in the file. The image part with relationship ID rid3 was not found in the file. Nicotine during development results in hypersensitive passive avoidance in adulthood E1 Birth P21 P90 NIC NIC PA Testing Time entry to dark chamber Time to enter dark chamber (sec) - Dams 200 ug/ml nicotine in drinking water dark compartment light compartment - Offspring weaned on water (3-4 weeks), tested as adults (3-5 months). King et al, J. Neuroscience, 2003

13 WT KO

14 The image part with relationship ID rid6 was not found in the file. The image part with relationship ID rid6 was not found in the file.. Constitutive β2 subunit knockout results in hypersensitive passive avoidance learning 120 Testing Time entry to dark chamber Time to enter dark (sec) training testing 20 0 wildtype knockout dark light compartment Picciotto et al, Nature, 1995

15 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?

16 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?

17 Inducible region specific expression Temporal-control of gene expression

18 Region-specific β2 nachr expression β2 +/- β2 -/- β2 tr(ct) β2 tr(vn) β2 tr(vta) β2 tr(fb) (CamKII-tTA) King et al, J. Neuroscience, 2003

19 wildtype β2 knockout transgenic Nicotine binding Rubidium efflux cortex in situ hybridization thalamus

20 Cortico-Thalamic Circuitry IV V VI Thalamic Reticular Neuron Thalamic Relay Neuron Sensory Input Adapted from: Miyata, M. (2007) Neurosci. Res. (59) pp Reichova, I. and Sherman, S.M. (2004) J. Neurophysiol. (92) pp

21 Cortico-Thalamic Circuitry a7 modulated synapse (Metherate) IV V VI Thalamic Reticular Neuron Thalamic Relay Neuron Sensory Input Adapted from: Miyata, M. (2007) Neurosci. Res. (59) pp Reichova, I. and Sherman, S.M. (2004) J. Neurophysiol. (92) pp

22 Cortico-Thalamic Circuitry IV V VI Thalamic Reticular Neuron Thalamic Relay Neuron β2* modulated synapse? Sensory Input Adapted from: Miyata, M. (2007) Neurosci. Res. (59) pp Reichova, I. and Sherman, S.M. (2004) J. Neurophysiol. (92) pp

23 Corticothalamic expression of β2 nachrs rescues adult passive avoidance King et al, J. Neurosci., 2003

24 Effect of developmental nicotine on PA depends on corticothalamic β2* nachrs E1 Birth P21 P90 NIC NIC PA Time to enter the dark chamber (sec) mean time to enter dark chamber (sec) Saline Nicotine Saline Nicotine KO *** CT Transgenics Train Test Heath et al, Neuropsychopharmacology, 2010

25 Other nachr subunits expressed α5: by corticothalamic neurons α5 In-situ hybridization Heath et al, Neuropsychopharmacology, 2010

26 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) pp ) α4β2α5 nachrs respond differently to intracellular Ca 2+ p(open) + open duration inter burst interval (Girod, R. et al. (1999) Ann. NY Acad. Sci. (868) pp )

27 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) pp ) Decreased function in corticothalamic terminal nachrs Thalamic synaptosomal 86 Rb + efflux (Brown, R.W. et al. (2007) J. Neurochem. (103) pp )

28 α5 knockout mice show partial hypersensitivity in passive avoidance Heath et al, Neuropsychopharmacology, 2010

29 Corticothalamic mice show rescued α4/β2/α5 nachrs Heath et al, Neuropsychopharmacology, 2010

30 Cortico-Thalamic Circuitry IV V VI Thalamic Reticular Neuron Thalamic Relay Neuron α4β2α5 modulated synapse Sensory Input Perinatal nicotine Adapted from: Miyata, M. (2007) Neurosci. Res. (59) pp Reichova, I. and Sherman, S.M. (2004) J. Neurophysiol. (92) pp

31 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?

32 Temporally-controlled gene expression King et al, J. Neurosci., 2003

33 β2* nachrs in corticothalamic neurons during development rescue PA mean time to enter dark chamber (sec) King et al, J. Neurosci., 2003

34 The β2 nachr transgene is expressed in corticothalamic efferents after P7 Heath et al, Neuropsychopharmacology, 2010

35 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

36 Nicotine affects passive avoidance when administered only posnatally E1 Birth P21 P90 NIC SAC SAC NIC PA Time to enter dark chamber (sec) train test * Sac-Sac Sac-Nic * Nic-Sac Nic-Nic conception birth weaning Day Day 0 Day 21 Saccharin nicotine Heath et al, Neuropsychopharmacology, 2010

37 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?

38 Developmental smoke exposure alters white matter maturation in internal capsule Myelinated Optic Nerve Jacobsen et al, J Neuroscience, 2007

39 What we think is happening Corticothalamic Glutamatergic Projection neuron X ACh Glutamatergic projection back to cortex Cholinergic afferent from hind brain Somatosensory neuron Thalamocortical relay cell

40 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

41 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 Collaborators Steve Buka J-P Changeux Al Collins Sharon Grady Cecelia Gotti Leslie Jacobsen Michael Marks Eric Nestler Tony George Stephanie O Malley Julie Staley Michele Zoli NIDA NIMH Funding TTURC NARSAD

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