Nicotinic α5 Subunits Drive Developmental Changes in the Activation and Morphology of Prefrontal Cortex Layer VI Neurons
Open accessAbstract
Background Nicotinic signaling in prefrontal layer VI pyramidal neurons is important to the function of mature attention systems. The normal incorporation of α5 subunits into α4β2* nicotinic acetylcholine receptors augments nicotinic signaling in these neurons and is required for normal attention performance in adult mice. However, the role of α5 subunits in the development of the prefrontal cortex is not known. Methods We sought to answer this question by examining nicotinic currents and neuronal morphology in layer VI neurons of medial prefrontal cortex of wild-type and α5 subunit knockout (α5−/−) mice during postnatal development and in adulthood. Results In wild-type but not in α5−/− mice, there is a developmental peak in nicotinic acetylcholine currents in the third postnatal week. At this juvenile time period, the majority of neurons in all mice have long apical dendrites extending into cortical layer I. Yet, by early adulthood, wild-type but not α5−/− mice show a pronounced shift toward shorter apical dendrites. This cellular difference occurs in the absence of genotype differences in overall cortical morphology. Conclusions Normal developmental changes in nicotinic signaling and dendritic morphology in prefrontal cortex depend on α5-comprising nicotinic acetylcholine receptors. It appears that these receptors mediate a specific developmental retraction of apical dendrites in layer VI neurons. This finding provides novel insight into the cellular mechanisms underlying the known attention deficits in α5−/− mice and potentially also into the pathophysiology of developmental neuropsychiatric disorders such as attention-deficit disorder and autism.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Key developing PFC circuitry is shaped by acetylcholine, and PFC pyramidal neurons depend on its proper signaling in terms of dendritic branching, spine formation and synaptogenesis.
“Key developing PFC circuitry is shaped by acetylcholine, and PFC pyramidal neurons depend on its proper signaling in terms of dendritic branching, spine formation and synaptogenesis [224–226].”
From Development of prefrontal cortex (2022) · cites this paper as [226]
The Results section reports that α5-containing nicotinic receptors influence dendritic complexity and developmental changes in the apical dendrites of medial PFC layer VI neurons. This supports a role for acetylcholine signaling in dendritic morphology, but the paper does not establish effects on spine formation or synaptogenesis, or extend its findings to all PFC pyramidal neurons. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Dynamic mapping of human cortical development during childhood through early adulthood
Gogtay, N., Giedd, J. N., Lusk, L., Hayashi, K. M., Greenstein, D., Vaituzis, A. C., Nugent, T. F., Herman, D. H., Clasen, L. S., Toga, A. W., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402680101 · Cited by 5,604 · see citing works
Hensch, T. K. (2004) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.27.070203.144327 · Cited by 1,300 · see citing works
Prefrontal cortex in the rat: Projections to subcortical autonomic, motor, and limbic centers
Gabbott, P. L. A., Warner, T. A., Jays, P. R. L., Salway, P., & Busby, S. J. (2005) · Journal of Comparative Neurology · doi:10.1002/cne.20738 · Cited by 1,227 · see citing works
Saccone, S. F., Hinrichs, A. L., Saccone, N. L., Chase, G. A., Konvicka, K., Madden, P. A. F., Breslau, N., Johnson, E. O., Hatsukami, D., Pomerleau, O., et al. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddl438 · Cited by 850 · see citing works
Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system
Taly, A., Corringer, P., Guédin, D., Lestage, P. J., & Changeux, J. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2927 · Cited by 706 · see citing works
Variants in Nicotinic Receptors and Risk for Nicotine Dependence
Bierut, L. J., Stitzel, J. A., Wang, J. C., Hinrichs, A. L., Grucza, R. A., Xuei, X., Saccone, N. L., Saccone, S. F., Bertelsen, S., Fox, L., et al. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2008.07111711 · Cited by 648 · see citing works
Prefrontal Acetylcholine Release Controls Cue Detection on Multiple Timescales
Parikh, V., Kozak, R., Martinez, V., & Sarter, M. (2007) · Neuron · doi:10.1016/j.neuron.2007.08.025 · Cited by 623 · see citing works
Chudasama, Y., Passetti, F., Rhodes, S. E. V., Lopian, D., Desai, A., & Robbins, T. W. (2003) · Behavioural Brain Research · doi:10.1016/j.bbr.2003.09.020 · Cited by 518 · see citing works
Muir, J. L., Everitt, B. J., & Robbins, T. W. (1996) · Cerebral Cortex · doi:10.1093/cercor/6.3.470 · Cited by 503 · see citing works
Critical periods during sensory development
Berardi, N., Pizzorusso, T., & Maffei, L. (2000) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(99)00047-1 · Cited by 490 · see citing works
Functional contributions of α5 subunit to neuronal acetylcholine receptor channels
Ramírez-Latorre, J. A., Yu, C., Qu, X., Perin, F., Karlin, A., & Role, L. W. (1996) · Nature · doi:10.1038/380347a0 · Cited by 397 · see citing works
Cholinergic Activity in Autism: Abnormalities in the Cerebral Cortex and Basal Forebrain
Perry, E. K., Lee, M., Martin-Ruiz, C. M., COURT, J. A., Volsen, S. G., Merrit, J., Folly, E. A., Iversen, P. E., Bauman, M. L., Perry, R. H., et al. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.7.1058 · Cited by 390 · see citing works
Liu, R.-J., & Aghajanian, G. K. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706679105 · Cited by 346 · see citing works
Zikopoulos, B., & Barbas, H. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.5511-05.2006 · Cited by 344 · see citing works
A lack of default network suppression is linked to increased distractibility in ADHD
Fassbender, C., Zhang, H., Buzy, W. M., Cortes, C. R., Mizuiri, D., Beckett, L., & Schweitzer, J. B. (2009) · Brain Research · doi:10.1016/j.brainres.2009.02.070 · Cited by 316 · see citing works
Zhang, Z., & Deschênes, M. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-16-06365.1997 · Cited by 279 · see citing works
Nashmi, R., Xiao, C., Deshpande, P., McKinney, S., Grady, S. R., Whiteaker, P., Huang, Q., McClure-Begley, T., Lindstrom, J. M., Labarca, C., et al. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2199-07.2007 · Cited by 274 · see citing works
Self-citationThomson (2010) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2010.00013 · Cited by 269 · see citing works
Attention function and dysfunction in autism
Allen, G. (2001) · Frontiers in Bioscience · doi:10.2741/allen · Cited by 256 · see citing works
Wada, E., McKinnon, D. H., Heinemann, S., Patrick, J., & Swanson, L. W. (1990) · Brain Research · doi:10.1016/0006-8993(90)90248-a · Cited by 254 · see citing works
Pugh, P., & Berg, D. K. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-02-00889.1994 · Cited by 252 · see citing works
Wilens, T. E., Biederman, J., Spencer, T. J., Bostic, J., Prince, J., Monuteaux, M. C., Soriano, J., Fine, C., Abrams, A., Rater, M., et al. (1999) · American Journal of Psychiatry · doi:10.1176/ajp.156.12.1931 · Cited by 230 · see citing works
Sequential interplay of nicotinic and GABAergic signaling guides neuronal development
Liu, Z., Neff, R. A., & Berg, D. K. (2006) · Science · doi:10.1126/science.1134246 · Cited by 227 · see citing works
Nicotinic Antagonists Enhance Process Outgrowth by Rat Retinal Ganglion Cells in Culture
Lipton, S. A., Frosch, M. P., Phillips, M. D., Tauck, D. L., & Aizenman, E. (1988) · Science · doi:10.1126/science.3344435 · Cited by 225 · see citing works
Passetti, F., Dalley, J. W., O’Connell, M. T., Everitt, B. J., & Robbins, T. W. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00183.x · Cited by 223 · see citing works
Corticothalamic feedback and sensory processing
Alitto, H. J., & Usrey, W. M. (2003) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(03)00096-5 · Cited by 220 · see citing works
Childhood psychiatric disorders as anomalies in neurodevelopmental trajectories
Shaw, P., Gogtay, N., & Rapoport, J. (2010) · Human Brain Mapping · doi:10.1002/hbm.21028 · Cited by 216 · see citing works
Saccone, N. L., Saccone, S. F., Hinrichs, A. L., Stitzel, J. A., Duan, W., Pergadia, M. L., Agrawal, A., Breslau, N., Grucza, R. A., Hatsukami, D., et al. (2009) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30828 · Cited by 215 · see citing works
The Nicotinic Acetylcholine Receptor Subunit α5 Mediates Short-Term Effects of Nicotine in Vivo
Salas, R., Orr‐Urtreger, A., Broide, R. S., Beaudet, A. L., Paylor, R. E., & Biasi, M. D. (2003) · Molecular Pharmacology · doi:10.1124/mol.63.5.1059 · Cited by 200 · see citing works
Tribollet, E., Bertrand, D., Marguerat, A., & Raggenbass, M. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2003.09.028 · Cited by 199 · see citing works
Tapia, L., Kuryatov, A., & Lindstrom, J. M. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.030445 · Cited by 196 · see citing works
Roles of Accessory Subunits in α4β2* Nicotinic Receptors
Kuryatov, A., Onksen, J., & Lindstrom, J. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.046789 · Cited by 195 · see citing works
Nicotinic acetylcholine receptor β2 subunits in the medial prefrontal cortex control attention
Guillem, K., Bloem, B., Poorthuis, R. B., Loos, M., Smit, A. B., Maskos, U., Spijker, S., & Mansvelder, H. D. (2011) · Science · doi:10.1126/science.1207079 · Cited by 191 · see citing works
Dalley, J. W. (2004) · Cerebral Cortex · doi:10.1093/cercor/bhh052 · Cited by 191 · see citing works
Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking
Stevens, V. L., Bierut, L. J., Talbot, J. T., Wang, J. C., Sun, J., Hinrichs, A. L., Thun, M. J., Goate, A., & Calle, E. E. (2008) · Cancer Epidemiology, Biomarkers & Prevention · doi:10.1158/1055-9965.epi-08-0585 · Cited by 190 · see citing works
Cortical Anatomy in Autism Spectrum Disorder: An In Vivo MRI Study on the Effect of Age
Raznahan, A., Toro, R., Daly, E., Robertson, D., Murphy, C. M., Deeley, Q., Bolton, P., Paus, T., & Murphy, D. (2009) · Cerebral Cortex · doi:10.1093/cercor/bhp198 · Cited by 174 · see citing works
Kuryatov, A., Berrettini, W., & Lindstrom, J. (2011) · Molecular Pharmacology · doi:10.1124/mol.110.066357 · Cited by 171 · see citing works
A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction
Hong, L. E., Hodgkinson, C. A., Yang, Y., Sampath, H., Ross, T. J., Buchholz, B., Salmeron, B. J., Srivastava, V., Thaker, G. K., Goldman, D. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004745107 · Cited by 164 · see citing works
Gilbert, S. J., Bird, G., Brindley, R., Frith, C. D., & Burgess, P. W. (2008) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2008.03.025 · Cited by 158 · see citing works
The Nicotinic Acetylcholine Receptor 5 Subunit Plays a Key Role in Attention Circuitry and Accuracy
Bailey, C. D. C., De Biasi, M., Fletcher, P. J., & Lambe, E. K. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.2258-10.2010 · Cited by 146 · see citing works
Self-citationMolecular analysis of nicotinic receptor expression in autism
Martin-Ruiz, C. M., Lee, M., Perry, R. H., Baumann, M., Court, J. A., & Perry, E. K. (2004) · Molecular Brain Research · doi:10.1016/j.molbrainres.2004.01.003 · Cited by 141 · see citing works
Mao, D., Perry, D. C., Yasuda, R. P., Wolfe, B. B., & Kellar, K. J. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05011.x · Cited by 133 · see citing works
Zhang, X., Liu, C., Miao, H., Gong, Z., & Nordberg, A. K. (1998) · International Journal of Developmental Neuroscience · doi:10.1016/s0736-5748(98)00044-6 · Cited by 123 · see citing works
Mercer, A., West, D. C., Morris, O. T., Kirchhecker, S., Kerkhoff, J. E., & Thomson, A. M. (2005) · Cerebral Cortex · doi:10.1093/cercor/bhi027 · Cited by 118 · see citing works
Healthy and abnormal development of the prefrontal cortex
Spencer‐Smith, M. M., & Anderson, V. A. (2009) · Developmental Neurorehabilitation · doi:10.3109/17518420903090701 · Cited by 113 · see citing works
Developmental Excitation of Corticothalamic Neurons by Nicotinic Acetylcholine Receptors
Kassam, S. M., Herman, P. M., Goodfellow, N. M., Alves, N. C., & Lambe, E. K. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.2645-08.2008 · Cited by 100 · see citing works
Self-citationProperties of Layer 6 Pyramidal Neuron Apical Dendrites
Ledergerber, D., & Larkum, M. E. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.2254-10.2010 · Cited by 93 · see citing works
Mechawar, N., & Descarries, L. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00389-x · Cited by 91 · see citing works
Local Connections to Specific Types of Layer 6 Neurons in the Rat Visual Cortex
Zarrinpar, A., & Callaway, E. M. (2005) · Journal of Neurophysiology · doi:10.1152/jn.00974.2005 · Cited by 90 · see citing works
Brown, R. W. B., Collins, A. C., Lindstrom, J. M., & Whiteaker, P. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04700.x · Cited by 88 · see citing works
Winzer‐Serhan, U. H., & Leslie, F. M. (2004) · The Journal of Comparative Neurology · doi:10.1002/cne.20357 · Cited by 79 · see citing works
Vaidya, C. J., Foss‐Feig, J. H., Shook, D. A., Kaplan, L. A., Kenworthy, L. E., & Gaillard, W. D. (2011) · Developmental Science · doi:10.1111/j.1467-7687.2011.01041.x · Cited by 70 · see citing works
Gotti, C., Moretti, M., Meinerz, N. M., Clementi, F., Gaimarri, A., Collins, A. C., & Marks, M. J. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.045203 · Cited by 68 · see citing works
Winterer, G., Mittelstraß, K., Giegling, I., Lamina, C., Fehr, C., Brenner, H., Breitling, L. P., Nitz, B., Raum, E., Müller, H., et al. (2010) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31126 · Cited by 66 · see citing works
Grady, S. R., Salminen, O., McIntosh, J. M., Marks, M. J., & Collins, A. C. (2009) · Journal of Molecular Neuroscience · doi:10.1007/s12031-009-9263-y · Cited by 61 · see citing works
Morphological Heterogeneity of Layer VI Neurons in Mouse Barrel Cortex
Chen, C.-C., Abrams, S., Pinhas, A., & Brumberg, J. (2009) · The Journal of comparative neurology · doi:10.1002/cne.21926 · Cited by 59 · see citing works
Ueno, K., Togashi, H., Matsumoto, M., Ohashi, S., Saito, H., & Yoshioka, M. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.302.1.95 · Cited by 56 · see citing works
Ferrer, I., Fábregues, I., & Condom, E. (1986) · PubMed · Cited by 52 · see citing works
Brumberg, J. C., Hamzei‐Sichani, F., & Yuste, R. (2003) · Journal of Neurophysiology · doi:10.1152/jn.01051.2002 · Cited by 52 · see citing works
Attention-deficit/hyperactivity disorder: A plausible mouse model?
Granon, S., & Changeux, J. (2006) · Acta Paediatrica · doi:10.1080/08035250600719747 · Cited by 49 · see citing works
Predominance of Late-Spiking Neurons in Layer VI of Rat Perirhinal Cortex
McGann, J. P., Moyer, J. R., & Brown, T. H. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-14-04969.2001 · Cited by 40 · see citing works
Kristt, D. A. (1979) · Anatomy and Embryology · doi:10.1007/bf00305161 · Cited by 31 · see citing works
Developmental Sex Differences in Nicotinic Currents of Prefrontal Layer VI Neurons in Mice and Rats
Alves, N. C., Bailey, C. D. C., Nashmi, R., & Lambe, E. K. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009261 · Cited by 29 · see citing works
Self-citationMize, R. R., Graham, S. K., & Cork, R. J. (2002) · Developmental Brain Research · doi:10.1016/s0165-3806(02)00350-4 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Development of prefrontal cortex
Kolk, S. M., & Rakic, P. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-021-01137-9 · Cited by 378 · see citing works
Adolescent neurodevelopment and substance use: receptor expression and behavioral consequences
Thorpe, H. H. A., Hamidullah, S., Jenkins, B. W., & Khokhar, J. Y. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107431 · Cited by 97 · see citing works
Cholinergic modulation of dopamine pathways through nicotinic acetylcholine receptors
de Kloet, S. F., Mansvelder, H. D., & De Vries, T. J. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.07.014 · Cited by 69 · see citing works
Galvin, V. C., Arnsten, A. F. T., & Wang, M. (2018) · Frontiers in Neural Circuits · doi:10.3389/fncir.2018.00067 · Cited by 25 · see citing works
Hoegberg, B. G., Lomazzo, E., Lee, N. H., & Perry, D. C. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.08.015 · Cited by 17 · see citing works
- Authors
- Bailey, C. D. C., Alves, N. C., Nashmi, R., De Biasi, M., & Lambe, E. K.
- Affiliations
- University of Toronto (CA)
- University of Victoria (CA)
- Corresponding author
- Lambe, Evelyn K.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 71
- Issue
- 2
- Pages
- 120-128
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3788582
- OpenAlex
- W2070469268
- Semantic Scholar
- 5471426a29a28a3cd108b107d567e8f03f26e515
- Cited by
- 69
- References
- 64
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 2 · 2023: 7 · 2022: 3 · 2021: 6 · 2020: 1 · 2019: 5 · 2018: 5 · 2017: 5 · 2016: 6 · 2015: 7 · 2014: 8 · 2013: 5 · 2012: 2
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research (89825)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- nicotinic acetylcholine receptors, alpha5 subunit, alpha4beta2 nicotinic receptor, prefrontal cortex, dendritic morphology, postnatal development, attention deficits, attention deficit disorder, autism spectrum disorder
- MeSH terms
- Animals, Male, Membrane Potentials, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Receptors, Nicotinic, Prefrontal Cortex, Mice, Knockout, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
