Connectome & Synaptome

The Machinery of Mind.  Within the 1.5-liter volume of one human brain, thousands of kilometers of electrically active axons and dendrites interconnect over a hundred billion highly diverse neurons at many hundreds of trillions of synapses.  Somehow, this 1.5-liter machine provides the physical substrate for every aspect of the human capability and experience.

The Synapse. Each individual synapse is itself a highly complex machine, comprising up to one hundred thousand diverse protein molecules, each of which may act as an independent “switch” to transduce cellular signals. It is the likely site of memory storage and retrieval.  Synaptic proteins vary widely from one neuron type to the next, being expressed from many alternative genes, in multiple splice variants, and subject to diverse post-translational modifications.  Synapses of the mammalian central nervous system are thus not only extremely numerous and extremely complex, but also extremely diverse.  This diversity poses great challenges but also great opportunities for advancing our understanding of neural circuit function (O’Rourke, Weiler, Micheva & Smith, 2012).

Some Numbers. The total number of synapses in one human brain approaches one thousand trillion, or 10^15.  The number of protein molecular “switches” (i.e., ion channels, receptors, transporters, and many other transduction molecules) at each of these synapses approaches 10^5.  The total number of synaptic switches per brain thus approaches 10^20.  This very large number is approximately the same as the total number of transistor “switches” in all of the computer chips on earth today, put together.  While digital computers are surely not apt metaphors for brains, comparisons of raw computational complexity would have to juxtapose one human brain to the entire global internet, rather than to any single digital computer.

Connectome. 1. The set of all synaptic connections in a specified organism or brain region (e.g., mouse connectome, neocortical connectome), or 2. A body of knowledge systematizing both constant and variable features of synaptic connectivity for a given organism or brain region.

Synaptome: 1. The set of all synapses in a specified organism or brain region (e.g., mouse synaptome, neocortical synaptome), or 2. A body of knowledge systematizing synaptic diversity.


O’Rourke, N.A., Weiler, N.C., Micheva, K.D. and Smith, S.J (2012) Deep molecular diversity of mammalian synapses: Why it matters and how to measure it.  Nature Reviews Neuroscience May 10. doi: 10.1038/nrn3170. [Epub ahead of print].

Tapia, J.C., Kasthuri, N., Hayworth, K., Schalek, R., Lichtman, J.W., Smith, S.J and Buchanan, J.  (2012) High contrast en bloc staining of neuronal tissue for field emission scanning electron microscopy.  Nature Protocols 7:193-206.

Kleinfeld, D., Bharioke, A., Blinder, P., Bock, D.D., Briggman, K.L., Chklovskii, D.B., Denk, W., Helmstaedter, M., Kaufhold, J.P., Lee, W.C., Meyer, H.S., Micheva, K.D., Oberlaender, M., Prohaska, S., Reid, R.C., Smith, S.J, Takemura, S., Tsai, P.S. and Sakmann, B. (2011) Large-scale automated histology in the pursuit of connectomes. J Neurosci. 31:16125-38. PubMed PMID: 22072665.

Robles, E., Smith, S.J and Baier H. (2011) Characterization of genetically targeted neuron types in the zebrafish optic tectum.  Frontiers Neural Circuits 5:1-14.

Micheva, K.D., Busse, B.L., Weiler, N.C., O'Rourke, N. and Smith, S.J (2010) Single-synapse analysis of a diverse synapse population: Proteomic imaging methods and markers.  Neuron 68:639-653.

Li, L., Tasic, B., Micheva, K.D., Ivanov, V.M., Spletter, M.L., Smith, S.J, Luo, L. (2010) Visualizing the distribution of synapses from individual neurons in the mouse brain.  PLoS One 5(7):e11503.

Isacoff, E. and Smith, S.J (2009) New Technologies. Curr. Opin. Neurobiol. 19:511-2.

Lichtman, J.W. and Smith, S.J (2008) Seeing Circuits Assemble.  Neuron 60:441-448.

Smith, S.J (2007) Circuit Reconstruction Tools Today.  Curr. Opin. In Neurobiol. 17:601-608.

Micheva, K.D., and Smith, S.J (2007)  Array tomography: A new tool for imaging the molecular architecture and ultrastructure of neural circuits.  Neuron 55:25-36.

Meyer, M.P., Niell, C.M, and Smith, S.J (2003) Brain Imaging: How stable are synaptic connections?  Curr. Biol., 13(5):R180-2.

Waters, J. and Smith, S.J (2002)  Vesicle pool partitioning influences presynaptic diversity and weighting in rat hippocampal synapses.  J. Physiol., 541(Pt 3):811-23.

Ahmari, S.E. and Smith, S.J (2002)  Minireview: Knowing a nascent synapse when you see it.  Neuron, 34, 333-336.

Hopf, F.W., Waters, J., Mehta, S. and Smith, S.J (2002)  Stability and plasticity of developing synapses in hippocampal neuronal cultures.  J. Neurosci. 22(3):775-781

Ziv. N.E. and Smith, S.J (1996)  Evidence for a role of dendritic filopodia in synaptogenesis and spine formation.  Neuron 17: 91-102.

Ryan, T.A., Ziv, N.E. and Smith, S.J  (1996) Potentiation of evoked vesicle turnover at individually resolved synaptic boutons.  Neuron 17: 125-134.

Dailey, M.E. and Smith, S.J (1996) The dynamics of dendritic structure in developing hippocampal slices.  J. Neurosci., 16: 2983-2994.