Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence

Journal name:
Nature Neuroscience
Volume:
14,
Pages:
417–419
Year published:
DOI:
doi:10.1038/nn.2770
Received
Accepted
Published online

Tobacco smoking and nicotine exposure during adolescence interfere with prefrontal cortex (PFC) development and lead to cognitive impairments in later life. The molecular and cellular underpinnings of these consequences remain elusive. We found that adolescent nicotine exposure induced lasting attentional disturbances and reduced mGluR2 protein and function on presynaptic terminals of PFC glutamatergic synapses. Restoring mGluR2 activity in vivo by local infusion of a group II mGluR agonist in adult rats that received nicotine as adolescents rescued attentional disturbances.

At a glance

Figures

  1. Adolescent nicotine exposure affects measures of attentional performance, mGluR2 levels and long-term function on the long term.
    Figure 1: Adolescent nicotine exposure affects measures of attentional performance, mGluR2 levels and long-term function on the long term.

    (a) Visuospatial divided and sustained attention is (accuracy, left) indicated by the percentage of correct stimulus detections (average of five baseline sessions; Supplementary Methods) and impulsive behavior is indicated by the number of prematurely expressed responses before stimulus onset (right) measured 5 weeks after adolescent (n = 11) or adult (n = 11) nicotine exposure. *P < 0.05, **P < 0.01. (b) Quantification of immunoblot analysis of synaptic mGluR2 expression (n = 8). #P < 0.1. (c) Time course of eEPSC amplitude reduction by LY379268 in adolescent nicotine- (black, n = 25) or saline-exposed rats (gray, n = 24); each data point is an average of seven eEPSCs. Insets, example eEPSC traces in control (a) and in the presence of LY379268 (b). Right, average of the last ten responses in the presence of LY379268. (d) mGluR2/3-dependent inhibition of eEPSC amplitudes was different as a result of adolescent nicotine treatment (saline, n = 39; nicotine, n = 47; F3,128 = 6.2, P = 0.0006), with no difference in rats treated as adults (saline, n = 22; nicotine, n = 26). Data represent mean ± s.e.m. All experiments were approved by the ethics committee of VU University Amsterdam.

  2. Short-term depression in mPFC is reduced 5 weeks after nicotine exposure during adolescence.
    Figure 2: Short-term depression in mPFC is reduced 5 weeks after nicotine exposure during adolescence.

    (a,d) Example of short-term plasticity recorded from a layer V pyramidal neuron after extracellular stimulation in layer II/III of adolescent nicotine- or saline-exposed animals. (b) Summary of short-term depression during ten stimuli (25–200-ms intervals), measured in adolescent-treated (left, F1,137 = 21.6, P < 0.001; saline, n = 10–26; nicotine, n = 10–23) and adult-treated rats (right, F1,255 = 4.57, P = 0.033; saline, n = 24; nicotine, n = 31). Average of the last three responses in the train was normalized to the first one for analysis. (c) mGluR group II/III antagonist MPPG reduced short-term plasticity in mPFC layer V pyramidal neurons (F2,124 = 7.03, P = 0.012; control, n = 11; 100 μM MPPG, n = 10–11; 200 μM MPPG, n = 6). Data represent mean ± s.e.m.

  3. Intra-mPFC infusion of mGluR2/3 agonist LY379268 reverses long-term attentional disturbances in rats exposed to nicotine as adolescents.
    Figure 3: Intra-mPFC infusion of mGluR2/3 agonist LY379268 reverses long-term attentional disturbances in rats exposed to nicotine as adolescents.

    (a) Infusion of the group II antagonist MPPG decreased divided and sustained attention (accuracy) in control animals. *P < 0.05. (b) LY379268 normalized the nicotine-induced disturbances in divided and sustained attention (accuracy) in rats exposed to nicotine as adolescents (dose, F1,10 = 4.08, P = 0.033), with no effect on rats exposed to saline as adolescents. (c,d) Impulsive behavior was not affected in control rats by MPPG (c) or in rats exposed to nicotine as adolescents by LY379268 (d), but was increased in saline-exposed rats (dose, F1,10 = 4.98, P = 0.018). Data represent mean ± s.e.m.

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Author information

  1. These authors contributed equally to this work.

    • Huibert D Mansvelder,
    • Tommy Pattij &
    • Sabine Spijker

Affiliations

  1. Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.

    • Danielle S Counotte,
    • Ka Wan Li,
    • Maarten Loos,
    • Roel C van der Schors,
    • August B Smit &
    • Sabine Spijker
  2. Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.

    • Natalia A Goriounova &
    • Huibert D Mansvelder
  3. Anatomy and Neurosciences, VU University Medical Center, Amsterdam, The Netherlands.

    • Dustin Schetters,
    • Anton N M Schoffelmeer &
    • Tommy Pattij

Contributions

D.S.C. and N.A.G. contributed equally to the experiments in this paper. D.S.C., K.W.L., A.B.S. and S.S. designed the molecular experiments. N.A.G. and H.D.M. designed the physiological experiments. D.S.C., A.N.M.S., S.S. and T.P. designed the behavioral experiments. D.S.C. and R.C.v.d.S. executed the molecular experiments. N.A.G. executed physiological experiments. D.S.C. and D.S. executed behavioral experiments. D.S.C., M.L. and S.S. analyzed molecular experiments. N.A.G. and H.D.M. analyzed physiological experiments. D.S.C. and T.P. analyzed behavioral experiments. D.S.C., H.D.M., T.P. and S.S. wrote the manuscript.

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The authors declare no competing financial interests.

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Supplementary information

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  1. Supplementary Text and Figures (2M)

    Supplementary Figures 1–10, Supplementary Tables 1–4, Supplementary Methods, Supplementary Results and Supplementary Discussion

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