Starburst Amacrine Cell
Starburst amacrine cells (SAC or SBAC) are, as the name would suggest, a subtype of retinal amacrine cells primarily identified by the characteristic “starbust” shape of the dendritic arbor. SACs are also noteworthy for being the only cell type in the retina to secrete two different neurotransmitters. They can secrete both the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) and the excitatory neurotransmitter ACh (acetylcholine), which is not secreted by any other cells in the retina. Two main roles for starburst amacrine cell have been characterized. SACs are (1) important in the computation of direction-selectivity and they also serve (2) an important function in the development of the retina. There are two subtypes of starburst amacrine cells, unambiguously defined by their differential stratification, morphology, connections, and roles in direction-selectivity.
Contents
Physiology
It has been known for almost five decades that there are ganglion cells in the retina that respond preferentially to a stimulus moving in a particular direction. These gangion cells, termed direction-selective ganglion cells (DSGC) have been extensively studied and characterized. However, it was not known for for many years whether the computation of direction selectivity occurred postsynaptically (i.e. in the ganglion cells themselves) or in some presynaptic partner of the ganglion cells. Starburst amacrine cells (SAC), which had been shown to be presynaptic to the DSGCs, were an ideal candidate for a presynaptic calculator of direction selectivity. Ultimately, it was shown that direction selectivity does occur in the distal dendrites of starburst amacrine cells.
Visual response properties
Generally speaking, starburst amacrine cells (SACs) respond to a visual stimulus that moves from the soma (cell body) towards the distal dendrites (centrifugal or CF motion) but not to a visual stimulus moving in the opposite direction (centripetal or CP motion). This property of SACs was established by two photon imaging.
The figure below shows a diagram of the visual response properties of a starburst amacrine cell (SAC). (A) Response to a flash of light on the distal dendrites. (B) Response to a proximal flash of light followed by a distal flash of light, simulating centrifugal motion. (C) Response to a distal flash of light followed by a more distal flash of light, simulating centripetal motion. Note that the SAC gives the greatest response to motion in the centrifugal direction. [2]
Cellular biophysics
Anatomy
Starburst amacrine cells have a very specific anatomy. Their descriptive name arose from the earliest images of this cell type, in which the characteristic 'starburst' branching of the dendritic arbor could be seen. There are two subytpes of amacrine cells, types a and b. In many categories of cells, classification of subtypes can be inexact and somewhat subjective. For SACs, however, the two subtypes display marked difference in both location, shape, and connections, with these structural differences playing a major role in their function. In fact, it was the differential stratification between subytpes that helped identify starburst amacrine cells as the acetylchole secreting cells in the retina.[3]
Location
Stratification
The distinct stratification of starburst amacrine cell subtypes was fundamental to the identification of starburst amacrine cells (SAC) as the source of acetylcholine in the retina. By the late 1970s, it was known that acetylcholine (ACh) was synthesized from choline in two different populations of cells in the retina. These ACh synthesizing cells were putatively identified as amacrine cells, since about half of them had cell bodies where one would normally expect to find amacrine cells, flanking the inner plexiform layer (IPL).[4] These were called type a starburst amacrine cells, since they were observed to branch in IPL sublamina a. The other half had their cell bodies in the ganglion cell layer (GCL) but did not appear to be ganglion cells. Since their cell bodies were "displaced" to the ganglion cell layer and they were observed to branch in IPL sublamina b, they are referred to as both type b or displaced starburst amacrine cells.[3] It had previously been shown that starburst amacrine cells also displayed the same localization pattern, and further study confirmed that the starburst amacrine cells were indeed the cholinergic cells in the retina.
Tiling
Another important aspect of SAC localization is that there is a high degree of overlap (often called tiling overlap) between the arbors of neighboring starburst amacrine cells.[5] The dendrites of many cell types will detect, during development, when they interact with dendrites of another cell and will stop growing. This results in a precise segregation of dendritic arbors that do not overlap. When this non-overlapping system happens, you end up with a tiling factor of one, meaning that the the total area covered by all the cells combined equals the total area. Many amacrine subytpes have a tiling factor of one. Starburst amacrine cells, however, can have a tiling factor of around 100, meaning that the overlap between dendritic arbors is so high that the sum of the area occuped by all cells is 100 times greater than the total area.
Shape
Starburst amacrine cells are named for the highly distinctive shape of their dendritic arbor. The average cell body diameter of a SAC is approximately 9 to 12 micrometers, while the dendritic field size ranges from about 150 micrometers (in the visual streak; see shape subsection below) to 600 micrometers (in the dorsal retina).[4] The dendritic arbor is sufficiently regular to allow for the precise characterization, which was formalized in the early 1980's.[4] The branching pattern originates from 4 or 5 "primary dendrites" extending from the cell body. Said branching is "concentrically and evenly distributed about the cell body" and there is almost no overlap of dendrites. The dendritic tree has been divided into three "distinct annular zones" as ones progresses from the cell body radially outwards.
Regions of the Dendritic Arbor
- Proximal Region (Proximal)
The first zone, closest to the cell body, is known as the proximal region. The dendrites here are relatively thin, with a diameter not greater than 1.5 micrometers at their origin. These dendrites taper as we progress radially outwards, until the region ends at the third or fourth branch point. The diameter of these dendrites is distinctly smaller in the visual streak (see shape subsection below), as opposed to gradually decreasing is size as we move away from the streak- as is the case for dendrites of the other two regions.[4]
- Intermediate Annular Region (Intermediate)
The dendrites will suddenly become more slender around the third or fourth branch point, which is where this region begins. This region is characterized by uniform dendrites.[4]
- Distal Annular Zone (Distal)
This zone is characterized by slender but uniform segments about 0.2 micrometers in diameter that are interrupted by "aperiodic preterminal and terminal varicosities and boutons," which range from 1 to 1.5 micrometers in diameter.[4] The distal zone has recently been shown to be the region of the dendritic arbor where direction selectivity takes place[6]. See the physiology section for more information.
Subtype Differences
There are some distinct structural differences between subtypes a and b, several of which can be seen from the figure at the beginning of this section. Generally speaking, the type a cell has a larger dendritic arbor and has a more regular branching pattern.[3] Type a has fewer "branches, spines and boutons in the distal dendritic zone"[3].
Relationship to Visual Streak
The shape of SACs is also highly correlated to their location in the retina with respect to the Visual Streak (or fovea, depending on the species).[3] In many species, the area of greatest acuity in the retina is not a single point (fovea), but rather an elongated "streak" running across the retina. In all species studied, the area of highest acuity (whether fovea or visual streak) boasts the highest concentration of cones, the lowest concentration of rods, and much smaller receptive field sizes for all cells. It is unsurprising that starburst amacrine cells also display structural changes as the perpendicular distance from the visual streak increases. Nearest the visual streak, both type a and b SACs have a relatively small cell body size and dendritic field diameter as well as a relatively high frequency of branching and frequency of synaptic boutons.[3] As we move perpendicularly away from the visual streak, cell body size and dendritic field diameter increases, while the frequency of branching and synaptic boutons decreases. (See figure.)
Connections
At its basic level, the “vertical” flow of information in the retina goes from photoreceptors (input) to bipolar cells to ganglion cells (output). Amacrine cells in general affect this circuit “horizontally” at the level of the bipolar to ganglion cell connection, typically receiving input from bipolar cells and making synapses on both bipolar cells and ganglion cells.
A typical neuron consists of a cell body, dendrites (dendritic arbor), and an axon (axonal arbor). Neurons will typically receive inputs on their dendrites (postsynaptic) and will output information on their axon (presynaptic). Many types of amacrine cells- including starburst amacrine cells- do not follow this structural or functional pattern. Many of these cells make both input and output connections along the same neuronal processes that show no distinction between axon and dendrite, and are nevertheless called "dendrites." Starburst amacrines are one of the types that do not have axons and both receive and transmit information via their dendrites.[6] In the figure below, you can see a comparison between three types of amacrine cells. [7]
Basic Circuitry
At the most basic level, starburst amacrine cells (SAC) will receive inputs from bipolar cells and will output information to ganglion cells. There are also connections (inhibitory) between starburst amacrine cells, whose dendritic arbors have substantial overlap. The circuit is mirrored in ON and OFF (types b and a) starburst amacrine cells. Here's how it works in an ON starburst amacrine cell. ON bipolar cells make excitatory synapses to an ON starburst amacrine cells. In the distal portions of the dendrites, the ON starburst amacrine cell makes inhibitory synapses to a direction-selective ganglion cell. For a more complete description of the function of this circuit, see the physiology section.
Direction Selectivity
Starburst amacrine cells have long been known to be the presynaptic partners to direction selective ganglion cells (DSGC), and in fact have been shown to be the cells that actually compute the direction selectivity.[8] Although this function is more completely described in the physiology section above, it has been recently shown that the asymmetric connectivity of the SACs may also play a role in these computations. In particular, a starburst amacrine cell will make synapses with many DSGCs, but the region of the SAC dendritic arbor that will synapse with a particular DSGC is dependent on the direction of selectivity of that particular DSGC. For example, the "upper" part of the dendritic arbor of a SAC will preferentially synapse with DSGCs having a "downward" direction selectivity.[9] (see figure below)
Molecules
Starburst amacrine cells (SAC) have two main distinguishing characteristics. The first is the typical "starburst" shape of the dendritic arbor, as was described above. The second is the fact that they release two neurotransmitters. It has long been known that starburst amacrine cells release acetylcholine (ACh). ACh is not a typical neurotransmitter in the retina, and in fact SACs are the only cells in the retina that have been shown to release it. The second neurotransmitter that starburst amacrine cells release is GABA, which was discovered in later studies of these cells.
Direction Selectivity
Development
History
Cholinergic Neurons
Starburst amacrine cells (SAC) were identified in the 1970s on the basis of the distinct "starburst" shape of their dendritic arbor. Later and completely independently, it was first discovered in 1976 that there were cells in the rabbit retina that secreted the neurotransmitter acetylcholine (ACh) and were thus referred to as cholinergic neurons. The most likely candidates were bipolar cells and amacrine cells, but it was not known at the time that the cholinergic neurons of the retina and SACs were one in the same. Later in 1976, it was shown that ganglion cells were postsynaptic to the cholinergic neurons.[10] By the 1980s, there was strong evidence that these two populations of cells were one and the same, largely on the basis of the stratification of subtypes. (See the structure section.)
In 2005 it was proven that there were direct connections between starburst cells.
Direction Selectivity
Molecular Specificity
Open Questions
As Richard Masland notes, there are "some interesting mysteries" regarding starburst amacrine cells (SAC).[11] SACs are especially noteworthy for secreting both acetylcholine (ACh) and GABA. Over the years the function of GABA has been extensively studied in these cells, especially in relation to the connections between SAC and direction-selective ganglion cells (DSGC). However, very little is known about the role of ACh, the second neurotransmitter. Although the release of GABA from SACs is known to be important in direction selectivity, "no one really knows why they [SAC] release acetyl choline- even though that’s how they were first discovered." [11]
Relation to Eyewire
One complete starburst amacrine cell has been reconstructed as part of the eyewire project.
References
- ↑ Keeley, P.W. et al. Dendritic spread and functional coverage of starburst amacrine cells. J. Comp. Neurol. 505, 539–546 (2007). Paywalled.
- ↑ Vaney, E.I., Sivyer, B., and W.R. Taylor (2012) Direction selectivity in the retina: symmetry and asymmetry in structure and function. Nature Reviews Neuroscience. 13: 194-208
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Famiglietti, E.V. (1985) Starburst amacrine cells: morphological constancy and systematic variation in the anisotropic field of rabbit retinal neurons. J. Neurosci. 5, 562–577
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Famiglietti, E. V., Jr. (1983) ON and OFF pathways through amacrine cells in mammalian retina: The synaptic connections of “starburst” amacrine cells. Vision Res. 23: 1265-1279. Paywalled.
- ↑ Tauchi, M. & Masland, R. H. The shape and arrangement of the cholinergic neurons in the rabbit retina. Proc. R. Soc. Lond. B 223, 101–191 (1984).
- ↑ 6.0 6.1 6.2 Euler, T., Detwiler, P.B., and Denk, W. (2002). Directionally selective calcium signals in dendrites of starburst amacrine cells. Nature 418, 845–852.
- ↑ 7.0 7.1 Schubert, T., and Euler, T. (2012). Retinal Processing: Global Players Like it Local. Curr. Biol. 20, 486-488. Paywalled.
- ↑ 8.0 8.1 Taylor, W. R. and R. G. Smith (2012) The role of starburst amacrine cells in visual signal processing. Visual Neuroscience. 29: 73-81. Paywalled.
- ↑ Cite error: Invalid
<ref>tag; no text was provided for refs namedBriggman - ↑ Masland RH, Ames A,, 3rd. Responses to acetylcholine of ganglion cells in an isolated mammalian retina. J Neurophysiol. 1976;39:1220–1235. Paywalled.
- ↑ 11.0 11.1 Conversation with Richard Masland 4/6/12
