They allow the same ganglion or amacrine cell to be visually targeted for recording. Even if several cell types express the fluorescent marker, one can use the anatomy of the cells to separate them, so that a single type can repeatedly be patched or imaged. An example where the expression is almost “pure” is the Jam-B cell, a ganglion cell type with a curious, wedge-of-pie shape and its own version of direction selectivity (Kim et al., BI-2536 2008). This cell had been reported in anatomical surveys, but no particular attention had been paid (indeed, one study—by the author of this review—mistakenly classified them as developmental accidents) until a mouse in which
they were selectively labeled was available. These mice will also be useful for validating the retina neurome, because they provide an additional criterion for what constitutes a cell type, but they have a limitation when it comes to accounting for the retinal cell populations. The creation of these mouse strains
is still a highly inexact science. This compromises the endgame—the attempt to learn when the census of cell types is complete. Most of the strains that exist so far show mixed expression of the marker in several cell types, or expression in only parts of a true cell population. And there is no way to know anything about the cells that are NOT labeled—no way to know where the labeled cell stands in the whole population of ganglion cells and how many unlabeled cell types remain. How many cells remain for which no one has yet hit upon an CYTH4 effective promoter strategy? What is the true mosaic of genetically marked cells, ON-1910 when one cannot count on reporter expression to mark all of the cell type’s members? Sooner or later, when the molecular fundamentals of gene expression are under better experimental control, a precise algorithm for the creation of cell type-specific lines will be devised and these obstacles will be overcome. In the meantime, other methods will also be required. An approach that avoids the sampling problem is provided by high throughput electron microscopy,
also known as connectomics (Anderson et al., 2009; Briggman and Denk, 2006; Denk et al., 2012; Denk and Horstmann, 2004; Kleinfeld et al., 2011; Lichtman and Sanes, 2008; Seung, 2009). The method, a descendent of early, hand-implemented, serial sectioning (Cohen and Sterling, 1991), requires still-developing computational methods, but even now it is extremely powerful. A small area of retina is serially sectioned and high-resolution images of every cell are reconstructed. In these images, the synapses between the cells can be identified and connections traced. Furthermore, the reconstruction can be made to include a cell of known physiological function, so that synaptic contributions to that particular cell’s response are identified (Briggman et al., 2011).