Abstract
Identifying the neuronal cell types that comprise the mammalian forebrain is a central unsolved problem in neuroscience. Global gene expression profiles offer a potentially unbiased way to assess functional relationships between neurons. Here, we carried out microarray analysis of 12 populations of neurons in the adult mouse forebrain. Five of these populations were chosen from cingulate cortex and included several subtypes of GABAergic interneurons and pyramidal neurons. The remaining seven were derived from the somatosensory cortex, hippocampus, amygdala and thalamus. Using these expression profiles, we were able to construct a taxonomic tree that reflected the expected major relationships between these populations, such as the distinction between cortical interneurons and projection neurons. The taxonomic tree indicated highly heterogeneous gene expression even within a single region. This dataset should be useful for the classification of unknown neuronal subtypes, the investigation of specifically expressed genes and the genetic manipulation of specific neuronal circuit elements.
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References
Douglas, R.J. & Martin, K.A. Neuronal circuits of the neocortex. Annu. Rev. Neurosci. 27, 419–451 (2004).
Kawaguchi, Y. & Kubota, Y. GABAergic cell subtypes and their synaptic connections in rat frontal cortex. Cereb. Cortex 7, 476–486 (1997).
Markram, H. et al. Interneurons of the neocortical inhibitory system. Nat. Rev. Neurosci. 5, 793–807 (2004).
Mott, D.D. & Dingledine, R. Interneuron diversity series: interneuron research–challenges and strategies. Trends Neurosci. 26, 484–488 (2003).
Feng, G. et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41–51 (2000).
Oliva, A.A., Jr., Jiang, M., Lam, T., Smith, K.L. & Swann, J.W. Novel hippocampal interneuronal subtypes identified using transgenic mice that express green fluorescent protein in GABAergic interneurons. J. Neurosci. 20, 3354–3368 (2000).
Chattopadhyaya, B. et al. Experience and activity-dependent maturation of perisomatic GABAergic innervation in primary visual cortex during a postnatal critical period. J. Neurosci. 24, 9598–9611 (2004).
Lopez-Bendito, G. et al. Preferential origin and layer destination of GAD65-GFP cortical interneurons. Cereb. Cortex 14, 1122–1133 (2004).
Xu, Q., Cobos, I., De La Cruz, E., Rubenstein, J.L. & Anderson, S.A. Origins of cortical interneuron subtypes. J. Neurosci. 24, 2612–2622 (2004).
Ferezou, I. et al. 5-HT3 receptors mediate serotonergic fast synaptic excitation of neocortical vasoactive intestinal peptide/cholecystokinin interneurons. J. Neurosci. 22, 7389–7397 (2002).
Galarreta, M., Erdelyi, F., Szabo, G. & Hestrin, S. Electrical coupling among irregular-spiking GABAergic interneurons expressing cannabinoid receptors. J. Neurosci. 24, 9770–9778 (2004).
Vruwink, M., Schmidt, H.H., Weinberg, R.J. & Burette, A. Substance P and nitric oxide signaling in cerebral cortex: anatomical evidence for reciprocal signaling between two classes of interneurons. J. Comp. Neurol. 441, 288–301 (2001).
Arlotta, P. et al. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron 45, 207–221 (2005).
Clarke, V.R. et al. A hippocampal GluR5 kainate receptor regulating inhibitory synaptic transmission. Nature 389, 599–603 (1997).
Burette, A. et al. Differential cellular and subcellular localization of AMPA receptor-binding protein and glutamate receptor-interacting protein. J. Neurosci. 21, 495–503 (2001).
Anderson, S.A. et al. Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late born striatal neurons. Neuron 19, 27–37 (1997).
Marin, O., Anderson, S.A. & Rubenstein, J.L. Origin and molecular specification of striatal interneurons. J. Neurosci. 20, 6063–6076 (2000).
Stuhmer, T., Anderson, S.A., Ekker, M. & Rubenstein, J.L. Ectopic expression of the Dlx genes induces glutamic acid decarboxylase and Dlx expression. Development 129, 245–252 (2002).
Colombo, E., Galli, R., Cossu, G., Gecz, J. & Broccoli, V. Mouse orthologue of ARX, a gene mutated in several X-linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons. Dev. Dyn. 231, 631–639 (2004).
Poirier, K. et al. Neuroanatomical distribution of ARX in brain and its localisation in GABAergic neurons. Brain Res. Mol. Brain Res. 122, 35–46 (2004).
Sah, P. & Faber, E.S. Channels underlying neuronal calcium-activated potassium currents. Prog. Neurobiol. 66, 345–353 (2002).
Robinson, R.B. & Siegelbaum, S.A. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu. Rev. Physiol. 65, 453–480 (2003).
Ashburner, M. et al. Gene ontology: tool for the unification of biology. Nat. Genet. 25, 25–29 (2000).
Ohno, S. Evolution by Gene Duplication (Springer-Verlag, New York, 1970).
Bairoch, A. et al. The universal protein resource (UniProt). Nucleic Acids Res. 33, D154–D159 (2005).
Takamori, S., Rhee, J.S., Rosenmund, C. & Jahn, R. Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons. Nature 407, 189–194 (2000).
Su, A.I. et al. Large-scale analysis of the human and mouse transcriptomes. Proc. Natl. Acad. Sci. USA 99, 4465–4470 (2002).
Su, A.I. et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc. Natl. Acad. Sci. USA 101, 6062–6067 (2004).
Evans, S.J. et al. DNA microarray analysis of functionally discrete human brain regions reveals divergent transcriptional profiles. Neurobiol. Dis. 14, 240–250 (2003).
McBain, C.J. & Fisahn, A. Interneurons unbound. Nat. Rev. Neurosci. 2, 11–23 (2001).
Diez del Corral, R. & Storey, K.G. Markers in vertebrate neurogenesis. Nat. Rev. Neurosci. 2, 835–839 (2001).
Dougherty, J.D. & Geschwind, D.H. Progress in realizing the promise of microarrays in systems neurobiology. Neuron 45, 183–185 (2005).
Gong, S. et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917–925 (2003).
Fukuchi-Shimogori, T. & Grove, E.A. Neocortex patterning by the secreted signaling molecule FGF8. Science 294, 1071–1074 (2001).
Lukaszewicz, A. et al. G1 phase regulation, area-specific cell cycle control, and cytoarchitectonics in the primate cortex. Neuron 47, 353–364 (2005).
O'Leary, D.D. & Nakagawa, Y. Patterning centers, regulatory genes and extrinsic mechanisms controlling arealization of the neocortex. Curr. Opin. Neurobiol. 12, 14–25 (2002).
Anderson, S., Mione, M., Yun, K. & Rubenstein, J.L. Differential origins of neocortical projection and local circuit neurons: role of Dlx genes in neocortical interneuronogenesis. Cereb. Cortex 9, 646–654 (1999).
Gonchar, Y. & Burkhalter, A. Three distinct families of GABAergic neurons in rat visual cortex. Cereb. Cortex 7, 347–358 (1997).
Kubota, Y. & Kawaguchi, Y. Three classes of GABAergic interneurons in neocortex and neostriatum. Jpn. J. Physiol. 44 (Suppl 2), S145–S148 (1994).
Gewin, V. A golden age of brain exploration. PLoS Biol. 3, e24 (2005).
Bussemaker, H.J., Li, H. & Siggia, E.D. Regulatory element detection using correlation with expression. Nat. Genet. 27, 167–171 (2001).
Roth, F.P., Hughes, J.D., Estep, P.W. & Church, G.M. Finding DNA regulatory motifs within unaligned noncoding sequences clustered by whole-genome mRNA quantitation. Nat. Biotechnol. 16, 939–945 (1998).
Tavazoie, S., Hughes, J.D., Campbell, M.J., Cho, R.J. & Church, G.M. Systematic determination of genetic network architecture. Nat. Genet. 22, 281–285 (1999).
Ihmels, J., Bergmann, S. & Barkai, N. Defining transcription modules using large-scale gene expression data. Bioinformatics 20, 1993–2003 (2004).
Ihmels, J. et al. Revealing modular organization in the yeast transcriptional network. Nat. Genet. 31, 370–377 (2002).
Hempel, C.M., Hartman, K.H., Wang, X.J., Turrigiano, G.G. & Nelson, S.B. Multiple forms of short-term plasticity at excitatory synapses in rat medial prefrontal cortex. J. Neurophysiol. 83, 3031–3041 (2000).
Paxinos, G. & Franklin, K.B.J. The Mouse Brain in Stereotaxic Coordinates (Academic Press, Boston, 2001).
Li, C. & Wong, W.H. Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc. Natl. Acad. Sci. USA 98, 31–36 (2001).
Esclapez, M., Tillakaratne, N.J., Tobin, A.J. & Houser, C.R. Comparative localization of mRNAs encoding two forms of glutamic acid decarboxylase with nonradioactive in situ hybridization methods. J. Comp. Neurol. 331, 339–362 (1993).
Jongen-Relo, A.L. & Amaral, D.G. A double labeling technique using WGA-apoHRP-gold as a retrograde tracer and nonisotopic in situ hybridization histochemistry for the detection of mRNA. J. Neurosci. Methods 101, 9–17 (2000).
Acknowledgements
We thank G. Turrigiano, P. Sengupta, D. Das and Y. Sugino for comments on the manuscript; R. Pavlyuk, Z. Zhao and Z. Meng for technical assistance; and J. Fahrenkrug (Bispebjerg University Hospital, Denmark) for a gift of VIP/PHI antibody. This work was supported by a grant from the National Eye Institute.
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Sugino, K., Hempel, C., Miller, M. et al. Molecular taxonomy of major neuronal classes in the adult mouse forebrain. Nat Neurosci 9, 99–107 (2006). https://doi.org/10.1038/nn1618
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DOI: https://doi.org/10.1038/nn1618