Deep molecular diversity of mammalian synapses: Why it matters and how to measure it

Nature Reviews Neuroscience

Volumn 13, Issue 6, 2012, Pages 365-379

  O'Rourke, Nancy A ^a   Weiler, Nicholas C ^a   Micheva, Kristina D ^a   Smith, Stephen J ^a  

^a STANFORD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMPA RECEPTOR; CALBINDIN; DISRUPTED IN SCHIZOPHRENIA 1 PROTEIN; GLUTAMATE RECEPTOR 1; GLUTAMATE RECEPTOR 2; GLUTAMATE RECEPTOR 3; GLUTAMATE RECEPTOR 7; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; NEUROTRANSMITTER; PARVALBUMIN; SYNAPTOBREVIN; SYNAPTOPHYSIN;

CENTRAL NERVOUS SYSTEM; CONNECTOME; DISEASE PREDISPOSITION; GABAERGIC TRANSMISSION; HUMAN; INTERNEURON; LONG TERM DEPRESSION; LONG TERM POTENTIATION; MAMMAL; MEMORY; MOLECULAR BIOLOGY; MOLECULAR DIVERSITY; MOLECULAR DYNAMICS; NEOCORTEX; NERVE CELL; NERVE CELL NETWORK; NERVE CELL PLASTICITY; NERVE FUNCTION; NEUROLOGIC DISEASE; NEUROSCIENCE; NEUROTRANSMISSION; NONHUMAN; POSTSYNAPTIC DENSITY; PRIORITY JOURNAL; PROTEOMICS; PYRAMIDAL NERVE CELL; REVIEW; SYNAPSE; SYNAPTIC TRANSMISSION; SYNAPTOME;

ANIMALS; BIODIVERSITY; HUMANS; MAMMALS; MEMORY; NERVOUS SYSTEM DISEASES; NEURAL PATHWAYS; NEURONAL PLASTICITY; PROTEOMICS; SYNAPSES; SYNAPTIC TRANSMISSION;

MAMMALIA;

EID: 84861231844     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/nrn3170     Document Type: Review

References (147)

1. Ramón y Cajal, S. The structure and connexions of neurons. Nobelprize.org [online], http://nobelprize.org/medicine/laureates/1906/cajal- lecture.pdf (1906).
2. Emes, R. D. et al. Evolutionary expansion and anatomical specialization of synapse proteome complexity. Nature Neurosci. 11, 799-806 (2008). (Pubitemid 351896675)
3. Takamori, S. et al. Molecular anatomy of a trafficking organelle. Cell 127, 831-846 (2006). (Pubitemid 44716256)
4. McPherson, P. S. Proteomic analysis of clathrin-coated vesicles. Proteomics 10, 4025-4039 (2010).
5. Collins, M. O. et al. Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome. J. Neurochem. 97 (Suppl. 1), 16-23 (2006).
6. Dosemeci, A. et al. Composition of the synaptic PSD-95 complex. Mol. Cell Proteomics 6, 1749-1760 (2007). (Pubitemid 350031676)
7. Peng, J. et al. Semiquantitative proteomic analysis of rat forebrain postsynaptic density fractions by mass spectrometry. J. Biol. Chem. 279, 21003-21011 (2004). (Pubitemid 38656501)
8. Schrimpf, S. P. et al. Proteomic analysis of synaptosomes using isotope-coded affinity tags and mass spectrometry. Proteomics 5, 2531-2541 (2005). (Pubitemid 40966480)
9. Filiou, M. D. et al. Profiling of mouse synaptosome proteome and phosphoproteome by IEF. Electrophoresis 31, 1294-1301 (2010).
10. Cheng, D. et al. Relative and absolute quantification of postsynaptic density proteome isolated from rat forebrain and cerebellum. Mol. Cell. Proteomics 5, 1158-1170 (2006). (Pubitemid 43985938)
11. Grønborg, M. et al. Quantitative comparison of glutamatergic and GABAergic synaptic vesicles unveils selectivity for few proteins including MAL2, a novel synaptic vesicle protein. J. Neurosci. 30, 2-12 (2010).
12. Selimi, F., Cristea, I. M., Heller, E., Chait, B. T. & Heintz, N. Proteomic studies of a single CNS synapse type: the parallel fiber/purkinje cell synapse. PLoS Biol. 7, e83 (2009).
13. Gong, S. et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917-925 (2003). (Pubitemid 37376918)
14. Lein, E. S. et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445, 168-176 (2007). (Pubitemid 46095716)
15. Fremeau, R. T. Jr et al. The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron 31, 247-260 (2001). (Pubitemid 32762978)
16. Ferraguti, F. & Shigemoto, R. Metabotropic glutamate receptors. Cell Tissue Res. 326, 483-504 (2006). (Pubitemid 44435821)
17. Shigemoto, R. et al. Target-cell-specific concentration of a metabotropic glutamate receptor in the presynaptic active zone. Nature 381, 523-525 (1996). (Pubitemid 26170930)
18. Miyata, M. Distinct properties of corticothalamic and primary sensory synapses to thalamic neurons. Neurosci. Res. 59, 377-382 (2007). (Pubitemid 350007816)
19. Fioravante, D. & Regehr, W. G. Short-term forms of presynaptic plasticity. Curr. Opin. Neurobiol. 21, 269-274 (2011).
20. Wang, Y. et al. Heterogeneity in the pyramidal network of the medial prefrontal cortex. Nature Neurosci. 9, 534-542 (2006).
21. Groh, A. et al. Cell-type specific properties of pyramidal neurons in neocortex underlying a layout that is modifiable depending on the cortical area. Cereb. Cortex 20 826-836 2009).
22. 2+ buffer saturation underlies paired pulse facilitation in calbindin-D28k-containing terminals. Neuron 38, 79-88 (2003). (Pubitemid 36423355)
23. 2+ buffers and synaptic efficacy. Cell Calcium 37, 489-495 (2005). (Pubitemid 40458447)
24. Caillard, O. et al. Role of the calcium-binding protein parvalbumin in short-term synaptic plasticity. Proc. Natl Acad. Sci USA 97, 13372-13377 (2000).
25. Reyes, A. et al. Target-cell-specific facilitation and depression in neocortical circuits. Nature Neurosci. 1, 279-285 (1998). (Pubitemid 128712317)
26. De Gois, S. et al. Identification of endophilins 1 and 3 as selective binding partners for VGLUT1 and their co-localization in neocortical glutamatergic synapses: implications for vesicular glutamate transporter trafficking and excitatory vesicle formation. Cell. Mol. Neurobiol. 26, 679-693 (2006).
27. Voglmaier, S. M. et al. Distinct endocytic pathways control the rate and extent of synaptic vesicle protein recycling. Neuron 51, 71-84 (2006). (Pubitemid 43963342)
28. Mutch, S. A. et al. Protein quantification at the single vesicle level reveals that a subset of synaptic vesicle proteins are trafficked with high precision. J. Neurosci. 31, 1461-1470 (2011).
29. Bragina, L., Giovedi, S., Barbaresi, P., Benfenati, F. & Conti, F. Heterogeneity of glutamatergic and GABAergic release machinery in cerebral cortex: analysis of synaptogyrin, vesicle-associated membrane protein, and syntaxin. Neuroscience 165, 934-943 (2010).
30. Bragina, L. et al. Heterogeneity of glutamatergic and GABAergic release machinery in cerebral cortex. Neuroscience 146, 1829-1840 (2007). (Pubitemid 46795530)
31. Isaac, J. T. R., Ashby, M. C. & McBain, C. J. The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity. Neuron 54, 859-871 (2007). (Pubitemid 46907505)
32. Lu, W. et al. Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron 62, 254-268 (2009).
33. Savtchouk, I. & Liu, S. J. Remodeling of synaptic AMPA receptor subtype alters the probability and pattern of action potential firing. J. Neurosci. 31, 501-511 (2011).
34. Cull-Candy, S. G. & Leszkiewicz, D. N. Role of distinct NMDA receptor subtypes at central synapses. Sci. STKE, re16 (2004).
35. Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B. & Seeburg, P. H. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529-540 (1994). (Pubitemid 24100885)
36. Brickley, S. G., Misra, C., Mok, M. H. S., Mishina, M. & Cull-Candy, S. G. NR2B and NR2D subunits coassemble in cerebellar Golgi cells to form a distinct NMDA receptor subtype restricted to extrasynaptic sites. J. Neurosci. 23, 4958-4966 (2003). (Pubitemid 36793222)
37. Granger, A. J., Gray, J. A., Lu, W. & Nicoll, R. A. Genetic analysis of neuronal ionotropic glutamate receptor subunits. J. Physiol. 589, 4095-4101 (2011).
38. Luscher, B., Fuchs, T. & Kilpatrick, C. L. GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron 70, 385-409 (2011).
39. Sassoè-Pognetto, M. Understanding the molecular diversity of GABAergic synapses. Front. Cell. Neurosci. 5, 4 (2011).
40. Klausberger, T., Roberts, J. D. B. & Somogyi, P. Cell type-and input-specific differences in the number and subtypes of synaptic GABAA receptors in the hippocampus. J. Neurosci. 22, 2513-2521 (2002). (Pubitemid 37465800)
41. Freund, T. F. & Katona, I. Perisomatic inhibition. Neuron 56, 33-42 (2007). (Pubitemid 47484182)
42. Rudolph, U., Crestani, F. & Möhler, H. GABAA receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol. Sci. 22, 188-194 (2001). (Pubitemid 32244305)
43. Hull, C., Isaacson, J. S. & Scanziani, M. Postsynaptic mechanisms govern the differential excitation of cortical neurons by thalamic inputs. J. Neurosci. 29, 9127-9136 (2009).
44. Burnashev, N., Monyer, H., Seeburg, P. H. & Sakmann, B. Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 8, 189-198 (1992).
45. 2+ permeability of AMPA-type glutamate receptor channels in neocortical neurons caused by differential GluR-B subunit expression. Neuron 12, 1281-1289 (1994).
46. Hestrin, S. Different glutamate receptor channels mediate fast excitatory synaptic currents in inhibitory and excitatory cortical neurons. Neuron 11, 1083-1091 (1993). (Pubitemid 24015282)
47. Vicini, S. et al. Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. J. Neurophysiol. 79, 555-566 (1998). (Pubitemid 28095877)
48. Kumar, S. S. & Huguenard, J. R. Pathway-specific differences in subunit composition of synaptic NMDA receptors on pyramidal neurons in neocortex. J. Neurosci. 23, 10074-10083 (2003). (Pubitemid 37392554)
49. Nyíri, G., Freund, T. F. & Somogyi, P. Input-dependent synaptic targeting of α2-subunit-containing GABAA receptors in synapses of hippocampal pyramidal cells of the rat. Eur. J. Neurosci. 13, 428-442 (2001). (Pubitemid 32158775)
50. Kato, A. S., Gill, M. B., Yu, H., Nisenbaum, E. S. & Bredt, D. S. TARPs differentially decorate AMPA receptors to specify neuropharmacology. Trends Neurosci. 33, 241-248 (2010).
51. Bιοque, J.-C. et al. Synapse-specific regulation of AMPA receptor function by PSD-95. Proc. Natl Acad. Sci. USA 103, 19535-19540 (2006). (Pubitemid 46026066)
52. Elias, G. M. & Nicoll, R. A. Synaptic trafficking of glutamate receptors by MAGUK scaffolding proteins. Trends Cell Biol. 17, 343-352 (2007). (Pubitemid 47102201)
53. Costa-Mattioli, M., Sossin, W. S., Klann, E. & Sonenberg, N. Translational control of long-lasting synaptic plasticity and memory. Neuron 61, 10-26 (2009).
54. Ho, V. M., Lee, J. & Martin, K. C. The cell biology of synaptic plasticity. Science 334, 623-628 (2011).
55. Valles, A. et al. Genomewide analysis of rat barrel cortex reveals time-and layer-specific mRNA expression changes related to experience-dependent plasticity. J. Neurosci. 31, 6140-6158 (2011).
56. Shepherd, J. D. & Bear, M. F. New views of Arc, a master regulator of synaptic plasticity. Nature Neurosci. 14, 279-284 (2011).
57. Bliss, T. & Lømo, T. Long-lasting potentiation of synaptic transmission in the dentate gyrus of the rat following selective depletion of monoamines. J. Physiol. 232, 331-356 (1973).
58. Dudek, S. M. & Bear, M. F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc. Natl Acad. Sci. USA 89, 4363-4367 (1992).
59. Malenka, R. C. & Bear, M. F. LTP and LTD: an embarrassment of riches. Neuron 44, 5-21 (2004). (Pubitemid 39348827)
60. Busetto, G., Higley, M. J. & Sabatini, B. L. Developmental presence and disappearance of postsynaptically silent synapses on dendritic spines of rat layer 2/3 pyramidal neurons. J. Physiol. 586, 1519-1527 (2008). (Pubitemid 351404957)
61. Ashby, M. C. & Isaac, J. T. R. Maturation of a recurrent excitatory neocortical circuit by experience-dependent unsilencing of newly formed dendritic spines. Neuron 70, 510-521 (2011).
62. Emond, M. R. et al. AMPA receptor subunits define properties of state-dependent synaptic plasticity. J. Physiol. 588, 1929-1946 (2010).
63. Kelly, L., Farrant, M. & Cull-Candy, S. G. Synaptic mGluR activation drives plasticity of calcium-permeable AMPA receptors. Nature Neurosci. 12, 593-601 (2009).
64. Miyashita, T., Kubik, S., Lewandowski, G. & Guzowski, J. F. Networks of neurons, networks of genes: an integrated view of memory consolidation. Neurobiol. Learn. Mem. 89, 269-284 (2008). (Pubitemid 351318264)
65. Rial Verde, E. M., Lee-Osbourne, J., Worley, P. F., Malinow, R. & Cline, H. T. Increased expression of the immediate-early gene arc/arg3.1 reduces AMPA receptor-mediated synaptic transmission. Neuron 52, 461-474 (2006). (Pubitemid 44667435)
66. Béïque, J.-C., Na, Y., Kuhl, D., Worley, P. F. & Huganir, R. L. Arc-dependent synapse-specific homeostatic plasticity. Proc. Natl Acad. Sci. USA 108, 816-821 (2011).
67. Shi, S., Hayashi, Y., Esteban, J. A. & Malinow, R. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105, 331-343 (2001). (Pubitemid 32455340)
68. Li, P., Rudolph, U. & Huntsman, M. M. Long-term sensory deprivation selectively rearranges functional inhibitory circuits in mouse barrel cortex. Proc. Natl Acad. Sci. USA 106, 12156-12161 (2009).
69. Feldman, D. E. Synaptic mechanisms for plasticity in neocortex. Annu. Rev. Neurosci. 32, 33-55 (2009).
70. Sjöstrom, P. J., Rancz, E. A., Roth, A. & Häusser, M. Dendritic excitability and synaptic plasticity. Physiol. Rev. 88, 769-840 (2008). (Pubitemid 351520092)
71. Maffei, A. The many forms and functions of long term plasticity at GABAergic synapses. Neural Plast. 2011, 254724 (2011).
72. Egger, V., Feldmeyer, D. & Sakmann, B. Coincidence detection and changes of synaptic efficacy in spiny stellate neurons in rat barrel cortex. Nature Neurosci. 2, 1098-1105 (1999). (Pubitemid 30126368)
73. Lüscher, C. & Huber, K. M. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65, 445-459 (2010).
74. Chevaleyre, V., Takahashi, K.A. & Castillo, P. E. Endocannabinoid-mediated synaptic plasticity in the CNS. Annu. Rev. Neurosci. 29, 37-76 (2006). (Pubitemid 44476839)
75. Renger, J. J. et al. Experience-dependent plasticity without long-term depression by type 2 metabotropic glutamate receptors in developing visual cortex. Proc. Natl Acad. Sci. USA 99, 1041-1046 (2002). (Pubitemid 34106632)
76. Crozier, R.A., Wang, Y., Liu, C.-H. & Bear, M. F. Deprivation-induced synaptic depression by distinct mechanisms in different layers of mouse visual cortex. Proc. Natl Acad. Sci. USA 104, 1383-1388 (2007). (Pubitemid 46184013)
77. Liu, C.-H., Heynen, A. J., Shuler, M. G. H. & Bear, M. F. Cannabinoid receptor blockade reveals parallel plasticity mechanisms in different layers of mouse visual cortex. Neuron 58, 340-345 (2008). (Pubitemid 351615182)
78. Coba, M. P. et al. Neurotransmitters drive combinatorial multistate postsynaptic density networks. Sci. Signal. 2, ra19 (2009).
79. Williams, M. E., de Wit, J. & Ghosh, A. Molecular mechanisms of synaptic specificity in developing neural circuits. Neuron 68, 9-18 (2010).
80. Zipursky, S. L. & Sanes, J. R. Chemoaffinity revisited: dscams, protocadherins, and neural circuit assembly. Cell 143, 343-353 (2010).
81. Dalva, M. B., McClelland, A. C. & Kayser, M. S. Cell adhesion molecules: signalling functions at the synapse. Nature Rev. Neurosci. 8, 206-220 (2007). (Pubitemid 46294663)
82. Biederer, T. & Stagi, M. Signaling by synaptogenic molecules. Curr. Opin. Neurobiol. 18, 261-269 (2008).
83. Sudhof, T. C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903-911 (2008).
84. Takeichi, M. The cadherin superfamily in neuronal connections and interactions. Nature Rev. Neurosci. 8, 11-20 (2007). (Pubitemid 46011995)
85. Arikkath, J. & Reichardt, L. F. Cadherins and catenins at synapses: roles in synaptogenesis and synaptic plasticity. Trends Neurosci. 31, 487-494 (2008).
86. Ango, F. et al. Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at Purkinje axon initial segment. Cell 119, 257-272 (2004). (Pubitemid 39360907)
87. Zonta, B. et al. A critical role for Neurofascin in regulating action potential initiation through maintenance of the axon initial segment. Neuron 69, 945-956 (2011).
88. Anderson, J. R. et al. Exploring the retinal connectome. Mol. Vis. 17, 355-379 (2011).
89. Anderson, J. R. et al. A computational framework for ultrastructural mapping of neural circuitry. PLoS Biol. 7, e1000074 (2009).
90. Helmstaedter, M., Briggman, K. L. & Denk, W. High-accuracy neurite reconstruction for high-throughput neuroanatomy. Nature Neurosci. 14, 1081-1088 (2011).
91. Bock, D. D. et al. Network anatomy and in vivo physiology of visual cortical neurons. Nature 471, 177-182 (2011).
92. Mishchenko, Y. et al. Ultrastructural analysis of hippocampal neuropil from the connectomics perspective. Neuron 67, 1009-1020 (2010).
93. Briggman, K. L., Helmstaedter, M. & Denk, W. Wiring specificity in the direction-selectivity circuit of the retina. Nature 471, 183-188 (2011).
94. Kleinfeld, D. et al. Large-scale automated histology in the pursuit of connectomes. J. Neurosci. 31, 16125-16138 (2011).
95. Ushkaryov, Y. A. & Sudhof, T. C. Neurexin III α: extensive alternative splicing generates membrane-bound and soluble forms. Proc. Natl Acad. Sci. USA 90, 6410-6414 (1993). (Pubitemid 23207222)
96. Ushkaryov, Y. A., Petrenko, A. G., Geppert, M. & Sudhof, T. C. Neurexins: synaptic cell surface proteins related to the α-latrotoxin receptor and laminin. Science 257, 50-56 (1992).
97. Ullrich, B., Ushkaryov, Y. A. & Sudhof, T. C. Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron 14, 497-507 (1995).
98. Song, J. Y., Ichtchenko, K., Sudhof, T. C. & Brose, N. Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc. Natl Acad. Sci. USA 96, 1100-1105 (1999). (Pubitemid 29072190)
99. Varoqueaux, F., Jamain, S. & Brose, N. Neuroligin 2 is exclusively localized to inhibitory synapses. Eur. J. Cell Biol. 83, 449-456 (2004). (Pubitemid 39433525)
100. Hoon, M. et al. Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina. Proc. Natl Acad. Sci. USA 108, 3053-3058 (2011).
101. Budreck, E. C. & Scheiffele, P. Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses. Eur. J. Neurosci. 26, 1738-1748 (2007). (Pubitemid 47493212)
102. Kohmura, N. et al. Diversity revealed by a novel family of cadherins expressed in neurons at a synaptic complex. Neuron 20, 1137-1151 (1998). (Pubitemid 28293131)
103. Wu, Q. & Maniatis, T. A striking organization of a large family of human neural cadherin-like cell adhesion genes. Cell 97, 779-790 (1999). (Pubitemid 29278051)
104. Zou, C., Huang, W., Ying, G. & Wu, Q. Sequence analysis and expression mapping of the rat clustered protocadherin gene repertoires. Neuroscience 144, 579-603 (2007). (Pubitemid 44855316)
105. Junghans, D. et al. Postsynaptic and differential localization to neuronal subtypes of protocadherin β16 in the mammalian central nervous system. Eur. J. Neurosci. 27, 559-571 (2008). (Pubitemid 351239306)
106. Ascoli, G. A. et al. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nature Rev. Neurosci. 9, 557-568 (2008). (Pubitemid 351873463)
107. Markram, H. et al. Interneurons of the neocortical inhibitory system. Nature Rev. Neurosci. 5, 793-807 (2004). (Pubitemid 39336216)
108. Miyazaki, T., Fukaya, M., Shimizu, H. & Watanabe, M. Subtype switching of vesicular glutamate transporters at parallel fibre-Purkinje cell synapses in developing mouse cerebellum. Eur. J. Neurosci. 17, 2563-2572 (2003). (Pubitemid 36819281)
109. Bayes, A. et al. Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nature Neurosci. 14, 19-21 (2010).
110. Jamain, S., Betancur, C., Giros, B., Leboyer, M. & Bourgeron, T. [Genetics of autism: from genome scans to candidate genes]. Med. Sci. (Paris) 19, 1081-1090 (2003) (in French). (Pubitemid 37432472)
111. Walsh, C. A., Morrow, E. M. & Rubenstein, J. L. Autism and brain development. Cell 135, 396-400 (2008).
112. Pinto, D. et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368-372 (2010).
113. Tabuchi, K. et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71-76 (2007). (Pubitemid 47538032)
114. Etherton, M. et al. Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proc. Natl Acad. Sci. USA 108, 13764-13769 (2011).
115. Jamain, S. et al. Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc. Natl Acad. Sci. USA 105, 1710-1715 (2008). (Pubitemid 351346579)
116. Peca, J. et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437-442 (2011).
117. St. Clair, D. et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336, 13-16 (1990). (Pubitemid 20207869)
118. Millar, J. K. et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet. 9, 1415-1423 (2000). (Pubitemid 30312490)
119. Brandon, N. J. et al. Understanding the role of DISC1 in psychiatric disease and during normal development. J. Neurosci. 29, 12768-12775 (2009).
120. Kirkpatrick, B. et al. DISC1 immunoreactivity at the light and ultrastructural level in the human neocortex. J. Comp. Neurol. 497, 436-450 (2006). (Pubitemid 43865795)
121. Glantz, L. A. & Lewis, D. A. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57, 65-73 (2000). (Pubitemid 30035660)
122. Kvajo, M. et al. A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. Proc. Natl Acad. Sci. USA 105, 7076-7081 (2008). (Pubitemid 351754532)
123. Hayashi-Takagi, A. et al. Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nature Neurosci. 13, 327-332 (2010).
124. Schurov, I. L., Handford, E. J., Brandon, N. J. & Whiting, P. J. Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment. Mol. Psychiatry 9, 1100-1110 (2004). (Pubitemid 40065455)
125. Palade, G. E. Electron microscope observations of internneuronal and neuromuscular synapses. Anat. Rec. 118, 335-336 (1954).
126. Chen, X. et al. Organization of the core structure of the postsynaptic density. Proc. Natl Acad. Sci. USA 105, 4453-4458 (2008). (Pubitemid 351754401)
127. Jones, B. W. et al. Retinal remodeling in the Tg P347L rabbit, a large-eye model of retinal degeneration. J. Comp. Neurol. 519, 2713-2733 (2011).
128. Micheva, K. D. & Smith, S. J. Array tomography: a new tool for imaging the molecular architecture and ultrastructure of neural circuits. Neuron 55, 25-36 (2007). (Pubitemid 46990817)
129. Micheva, K. D., Busse, B., Weiler, N. C., O'Rourke, N. & Smith, S. J. Single-synapse analysis of a diverse synapse population: proteomic imaging methods and markers. Neuron 68, 639-653 (2010).
130. Hell, S. W. & Wichmann, J. Breaking the diffraction resolution limit by stimulated emission: stimulated-emission-depletion fluorescence microscopy. Opt. Lett. 19, 780-782 (1994).
131. Rust, M. J., Bates, M. & Zhuang, X. Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nature Methods 3, 793-795 (2006). (Pubitemid 44445825)
132. Betzig, E. et al. Imaging intracellular fluorescent proteins at nanometer resolution. Science 313, 1642-1645 (2006). (Pubitemid 44414039)
133. Hess, S. T., Girirajan, T. P. & Mason, M. D. Ultra-high resolution imaging by fluorescence photoactivation localization microscopy. Biophys. J. 91, 4258-4272 (2006). (Pubitemid 44887284)
134. Dani, A., Huang, B., Bergan, J., Dulac, C. & Zhuang, X. Superresolution imaging of chemical synapses in the brain. Neuron 68, 843-856 (2010).
135. Buckers, J., Wildanger, D., Vicidomini, G., Kastrup, L. & Hell, S. W. Simultaneous multi-lifetime multi-color STED imaging for colocalization analyses. Opt. Express 19, 3130-3143 (2011).
136. Bates, M., Huang, B., Dempsey, G. T. & Zhuang, X. Multicolor super-resolution imaging with photo-switchable fluorescent probes. Science 317, 1749-1753 (2007). (Pubitemid 47461839)
137. Sugino, K. et al. Molecular taxonomy of major neuronal classes in the adult mouse forebrain. Nature Neurosci. 9, 99-107 (2006). (Pubitemid 43011915)
138. Lichtman, J. W. & Denk, W. The big and the small: challenges of imaging the brain's circuits. Science 334, 618-623 (2011).
139. Jain, V., Seung, H. S. & Turaga, S. C. Machines that learn to segment images: a crucial technology for connectomics. Curr. Opin. Neurobiol. 20, 653-666 (2010).
140. Ramón y Cajal, S. Neuronismo o reticularismo? Las pruebas objetivas de la unidad anatómica de las células nerviosas. Archivos de Neurobiología 13 1-144 (1933) (in Spanish).
141. Micheva, K. D. & Beaulieu, C. An anatomical substrate for experience-dependent plasticity of the rat barrel field cortex. Proc. Natl Acad. Sci. USA 92, 11834-11838 (1995). (Pubitemid 26014204)
142. Stewart, W. W. Functional connections between cells as revealed by dye-coupling with a highly fluorescent naphthalimide tracer. Cell 14, 741-759 (1978).
143. Grutzendler, J., Kasthuri, N. & Gan, W. B. Long-term dendritic spine stability in the adult cortex. Nature 420, 812-816 (2002). (Pubitemid 36019628)
144. Trachtenberg, J. T. et al. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788-794 (2002). (Pubitemid 36019621)
145. Xu, T. et al. Rapid formation and selective stabilization of synapses for enduring motor memories. Nature 462, 915-919 (2009).
146. Yang, G., Pan, F. & Gan, W. B. Stably maintained dendritic spines are associated with lifelong memories. Nature 462, 920-924 (2009).
147. Matsuzaki, M. et al. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nature Neurosci. 4, 1086-1092 (2001). (Pubitemid 34116553)