Difference between revisions of "Starburst Amacrine Cell"

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[[Image:2007structure1.png|thumb|right|350px|Image of a starburst amacrine cell showing the "starburst" shape of the dendritic arbor<ref>Keeley, P.W. et al. Dendritic spread and functional coverage of starburst amacrine cells. J. Comp. Neurol. 505, 539–546 (2007).</ref>.]]
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'''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.   
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[[File:Keeley SACs.jpg|thumb|right|350px|Images of starburst amacrine cells showing the "starburst" shape of the dendritic arbor<ref>Keeley, P.W. et al. Dendritic spread and functional coverage of starburst amacrine cells. J. Comp. Neurol. 505, 539–546 (2007).</ref>.]]
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'''Starburst amacrine cells''' (SAC or SBAC) are, as the name would suggest, a subtype of retinal [[Amacrine Cell|amacrine cells]] primarily identified by the characteristic “starburst” shape of the [[Dendrite#Dendritic_Arbor|dendritic arbor]]. 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.   
  
  
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===Visual response properties===
 
===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.
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Generally speaking, starburst amacrine cells (SACs) respond to a visual stimulus that moves from the [[Cell Body|soma (cell body)]] towards the distal [[Dendrite|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.
 
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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. <ref name="2012b">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</ref>
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The figure below shows a diagram of the visual response properties of a starburst amacrine cell. (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. <ref name="2012b">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</ref>
  
[[Image:fig2012.png|center]]
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[[File:DS Responses in SACs.jpg|400px|center]]
  
 
===Cellular biophysics===
 
===Cellular biophysics===
  
Starburst amacrine cells (SAC) are the only cells in the retina that have been shown to release two neurotransmitters. They secrete the normally inhibitory neurotransmitter GABA and the excitatory neurotransmitter ACh. Release of both neurotransmitters is monosynaptic and mediated by calcium. However, it has also been shown that these two neurotransmitters are not released together. The release properties of the two transmitters are affected differently by alterations in the buffer, specific calcium blockers, and extracellular concentrations.  
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Starburst amacrine cells are the only cells in the retina that have been shown to release two neurotransmitters. They secrete the normally inhibitory neurotransmitter GABA and the excitatory neurotransmitter ACh. Release of both neurotransmitters is monosynaptic and mediated by calcium. However, it has also been shown that these two neurotransmitters are not released together. The release properties of the two transmitters are affected differently by alterations in the buffer, specific calcium blockers, and extracellular concentrations.  
  
 
'''<i>Connection Asymmetry</i>'''
 
'''<i>Connection Asymmetry</i>'''
  
Direction selective ganglion cells (DSGCs) receive inputs from many starburst amacrine cells, but the type or strength of these connections are importantly asymmetric. DSGCs have a preferred direction and a null direction, meaning that they will respond only to a visual stimuli that moves in the preferred direction.  
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[[On-Off_Direction-Selective_Ganglion_Cell|Direction selective ganglion cells (DSGCs)]] receive inputs from many starburst amacrine cells, but the type or strength of these connections are importantly asymmetric. DSGCs have a preferred direction and a null direction, meaning that they will respond only to a visual stimuli that moves in the preferred direction.  
  
* <b>GABA:</b> If you stimulate (depolarize) a starburst amacrine cell that first connects with a DSGC along its <i>null direction</i>, you inhibit the DSGC in a GABA-mediated way. If you depolarize a starburst amacrine cell that first connects with a DSGC along the <i>preferred direction</i>, you don't get inhibition. Thus, DSGCs recieve asymmetric GABAergic (GABA-mediated) inputs from SACs.
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* <b>GABA:</b> If you stimulate (depolarize) a starburst amacrine cell that first connects with a DSGC along its <i>null direction</i>, you inhibit the DSGC in a GABA-mediated way. If you depolarize a starburst amacrine cell that first connects with a DSGC along the <i>preferred direction</i>, you don't get inhibition. Thus, DSGCs recieve asymmetric GABAergic (GABA-mediated) inputs from SACs.<ref name="2012a"></ref>
  
* <b>ACh:</b> If you stimulate (depolarize) a starburst amacrine cell that connects to a DSGC in <i>any direction</i> you will excite the DSGC in an ACh-dependent way. Thus, DSGCs receive symmetric cholinergic (ACh-mediated) synapses from SACs.
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* <b>ACh:</b> If you stimulate (depolarize) a starburst amacrine cell that connects to a DSGC in <i>any direction</i> you will excite the DSGC in an ACh-dependent way. Thus, DSGCs receive symmetric cholinergic (ACh-mediated) synapses from SACs.<ref name="2012a"></ref>
  
 
The asymmetric GABA connections are essential for the computation of direction selectivity. If you block the GABA channels in the DSGC, you ablate direction selectivity. However, if you just block the cholinergic channels in the DSGC you don't ablate direction selectivity but merely reduce all responses by about half. Thus, the exact cellular function of ACh is still unknown.
 
The asymmetric GABA connections are essential for the computation of direction selectivity. If you block the GABA channels in the DSGC, you ablate direction selectivity. However, if you just block the cholinergic channels in the DSGC you don't ablate direction selectivity but merely reduce all responses by about half. Thus, the exact cellular function of ACh is still unknown.
  
 
==Anatomy==
 
==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 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 acetylcholine secreting cells in the retina.<ref name="1985a"></ref>  
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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.<ref name="1983b">Famiglietti EV., Jr. ‘Starburst’ amacrine cells and cholinergic neurons: mirror-symmetric on and off amacrine cells of rabbit retina. Brain Res. 1983;261:138–144.</ref> In many categories of cells, classification of subtypes can be inexact and somewhat subjective. For SACs, however, the two subtypes display marked difference in 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 acetylcholine secreting cells in the retina.<ref name="1985a"></ref>  
 
[[Image:1985c.png|thumb|center|700px|The anatomical differences between type a and b starburst amacrine cells. Note (A) the differences in dendritic arbor diameter, (B) branching regularity, and (C,D) stratification.<ref name="1985a">Famiglietti, E.V. (1985) [http://www.jneurosci.org/content/5/2/562.full.pdf Starburst amacrine cells: morphological constancy and systematic variation in the anisotropic field of rabbit retinal neurons]. J. Neurosci. 5, 562–577</ref>]]
 
[[Image:1985c.png|thumb|center|700px|The anatomical differences between type a and b starburst amacrine cells. Note (A) the differences in dendritic arbor diameter, (B) branching regularity, and (C,D) stratification.<ref name="1985a">Famiglietti, E.V. (1985) [http://www.jneurosci.org/content/5/2/562.full.pdf Starburst amacrine cells: morphological constancy and systematic variation in the anisotropic field of rabbit retinal neurons]. J. Neurosci. 5, 562–577</ref>]]
  
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<i>'''Stratification'''</i>
 
<i>'''Stratification'''</i>
  
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).<ref name="1983a">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}}</ref> These were called <b>type a starburst amacrine cells</b>, 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 <b> type b</b> or <b>displaced starburst amacrine cells.</b><ref name="1985a"></ref> 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.
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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).<ref name="1983a">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.</ref> These were called <b>type a (OFF) starburst amacrine cells</b>, 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 <b> type b (ON)</b> or <b>displaced starburst amacrine cells.</b><ref name="1985a"></ref> 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.
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[[Image:SAC Tiling.jpg |thumb| right|200px|Tiling of SACs<ref name="2012b"></ref>]]
  
 
<i>'''Tiling'''</i>
 
<i>'''Tiling'''</i>
  
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.<ref>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).</ref> 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.
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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.<ref>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).</ref> 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 subtypes 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. A high tiling factor can also be referred to as high eccentricity. In the figure to the right, each color represents a preferred direction and solid circles represent the soma of individual SACs. Note the degree of overlap between neighboring cells.
  
 
===Shape===
 
===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).<ref name="1983a"></ref> The dendritic arbor is sufficiently regular to allow for the precise characterization, which was formalized in the early 1980's.<ref name="1983a"></ref> 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.  
 
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).<ref name="1983a"></ref> The dendritic arbor is sufficiently regular to allow for the precise characterization, which was formalized in the early 1980's.<ref name="1983a"></ref> 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.  
  
[[Image:figlocations.png|thumb|right|350px|A picture of the dendritic arbor of a starburst amacrine cell, with the regions labeled. Note that output signals only occur from the distal region.<ref name="2002nature"></ref>]]
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[[File:SAC regions.jpg|thumb|right|400px|A picture of the dendritic arbor of a starburst amacrine cell, with the regions labeled. Note that output signals only occur from the distal region.<ref name="2002nature"></ref>]]
  
 
<b><i>Regions of the Dendritic Arbor</i></b>
 
<b><i>Regions of the Dendritic Arbor</i></b>
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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.
 
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.<ref name="2002nature">Euler, T., Detwiler, P.B., and Denk, W. (2002). [http://retina.anatomy.upenn.edu/pdfiles/5908.pdf Directionally selective calcium signals in dendrites of starburst amacrine cells]. Nature 418, 845–852.</ref> In the figure below, you can see a comparison between three types of amacrine cells.  
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A typical neuron consists of a [[Cell Body|cell body]], [[Dendrite|dendrites (dendritic arbor)]], and an [[Axon|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.<ref name="2002nature">Euler, T., Detwiler, P.B., and Denk, W. (2002). [http://retina.anatomy.upenn.edu/pdfiles/5908.pdf Directionally selective calcium signals in dendrites of starburst amacrine cells]. Nature 418, 845–852.</ref> In the figure below, you can see a comparison between three types of amacrine cells.  
 
<ref name="2010a">Schubert, T., and Euler, T. (2012). Retinal Processing: Global Players Like it Local. Curr. Biol. 20, 486-488. {{paywalled}}</ref>
 
<ref name="2010a">Schubert, T., and Euler, T. (2012). Retinal Processing: Global Players Like it Local. Curr. Biol. 20, 486-488. {{paywalled}}</ref>
[[Image:figconnections.png|thumb|center|500px|A diagram of the connections made by several types of amacrine cells. The starburst amacrine cell, shown on the right, is a type a SAC. Note the lack of an axon and the presence of outputs on the dendritic arbor.<ref name="2010a"></ref>]]
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[[File:Fig connections.jpg|thumb|center|500px|A diagram of the connections made by several types of amacrine cells. The starburst amacrine cell, shown on the right, is a type a SAC. Note the lack of an axon and the presence of outputs on the dendritic arbor.<ref name="2010a"></ref>]]
  
 
<b><i>Basic Circuitry</i></b>
 
<b><i>Basic Circuitry</i></b>
  
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.  
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At the most basic level, starburst amacrine cells will receive inputs from bipolar cells and will output information to [[Ganglion Cell|ganglion cells]]. There are also [[Synapse#Function|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.  
  
<b><i>Direction Selectivity</i></b>
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==Direction Selectivity==
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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 ganglion cells, termed direction-selective ganglion cells 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, 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.
  
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.<ref name="2012a">Taylor, W. R. and R. G. Smith (2012) The role of starburst amacrine cells in visual signal processing. Visual Neuroscience. 29: 73-81. {{paywalled}}</ref> 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.<ref name="Briggman"/> (see figure below)
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[[Image:circuits.jpg|center|700px]]
[[Image:figdirections.png|thumb|center|350px|Starburst amacrine cell, showing preferential connectivity with particular direction selective ganglion cells. The colors represent the direction of selectivity of postsynaptic ganglion cells. Note how the colors segregate into roughly four quadrants.<ref name="Briggman"></ref>]]
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Above we can see a diagram of the circuit elements involved in direction selectivity. Note that the ON and OFF subtypes of SACs have their cell bodies flanking opposite sides of the inner plexiform layer (IPL). The ganglion cells all have their cell bodies below the IPL in the ganglion cell layer (GCL), but where they send their projections is determined by whether their direction selectivity is ON or OFF. An ON direction selective cell will send its projections to sublamina b (the lower sublamina in this figure). Likewise, an ON starburst amacrine cell will send its projections to sublamina b<ref name="2012b"> An ON/OFF DSGC will send projections to both sublamina.</ref>  
  
===Suggested Reading===
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===Wiring Symmetry and Asymmetry===
Early characterization of SACs:
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* 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.
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==Molecules==
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Starburst amacrine cells have long been known to be the presynaptic partners to direction selective ganglion cells, and in fact have been shown to be the cells that actually compute the direction selectivity.<ref name="2012a">Taylor, W. R. and R. G. Smith (2012) The role of starburst amacrine cells in visual signal processing. Visual Neuroscience. 29: 73-81.</ref> 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 "rightmost" part of the dendritic arbor of a SAC will preferentially synapse with DSGCs having a "leftward" direction selectivity.<ref name="Briggman"/> (see figure below)
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 <i>two</i> 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.
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Another interesting fact is that, for reasons unknown, starburst amacrine cells contain GAD67 but not GAD65. GAD67 and 65 are the two different isoforms of glutamate decarboxylase, which is the biosynthetic enzyme necessary to synthesize GABA. This was an unexpected result because, in most other GABAergic cells, GAD67 is far more prevalent.  
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Let's consider the rightmost part of a SAC dendritic arbor. It will preferentially make synapses with a left-selective ganglion cell. This computes direction selectivity because when a stimulus moves in a rightward direction, the SAC is being centrifugally stimulated and will provide maximum inhibition. When light is moving in a leftward direction, the SAC is being centripetally stimulated and will provide minimum inhibition.
<ref name="iso">Brandon C, Criswell MH. Displaced starburst amacrine cells of the rabbit retina contain the 67-kDa isoform, but not the 65- kDa isoform, of glutamate decarboxylase. Vis Neurosci 1995; 12:1053-61.</ref>
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<i><b>Suggested Reading</b></i>
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[[File:SACDirections.jpg|thumb|center|350px|Starburst amacrine cell, showing preferential connectivity with particular direction selective ganglion cells. The colors represent the direction of selectivity of postsynaptic ganglion cells. Note how the colors segregate into roughly four quadrants.<ref name="Briggman">Briggman, K.L., Helmstaedter, M. & Denk, W. Wiring specificity in the direction-selectivity circuit of the retina. Nature 471, 183–188 (2011). </ref>]]
 
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Isoforms of GAD:
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* Brandon C, Criswell MH. Displaced starburst amacrine cells of the rabbit retina contain the 67-kDa isoform, but not the 65- kDa isoform, of glutamate decarboxylase. Vis Neurosci 1995; 12:1053-61.
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==Direction Selectivity==
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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.  
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[[Image:2012fig1.png|thumb|center|400px|A diagram of the connections made by a type a starburst amacrine cell.<ref name="2012a"></ref>]]
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<b><i>Suggested Reading</i></b>
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===Current Model===
  
Review:
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So how is direction selectivity computed? The image below diagrams the current prevailing model.<ref name="2012b"></ref> As discussed above, SACs receive inputs on their proximal dendrites- both excitatory synapses from bipolar cells and (GABAergic) inhibitory synapses from other starburst amacrine cells. They also make (GABAergic) inhibitory synapses on their distal dendrites both to other starburst amacrine cells and to direction selective ganglion cells. SACs will preferentially connect with DSGCs as described in the wiring symmetry subsection (not shown in this figure). Furthermore, a SAC will provide greater inhibition when visually stimulated by centrifugal motion compared to centripetal motion.
* 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
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==Development==
 
==Development==
The retinal circuitry of most mature organisms is notably different from the circuitry established during development. This early wiring is not simply an immature state of the developing system. Rather, specific connections and cellular properties are established during early development that are completely different from those properties seen in the mature system. In fact, this early circuitry must be "deconstructed" during postnatal development prior to completion of the final visual circuit. Starburst amacrine cells (SACs) have unique properties during development and play an important (but poorly understood) role in the signals generated by this early system.  
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The retinal circuitry of most mature organisms is notably different from the circuitry established during development. This early wiring is not simply an immature state of the developing system. Rather, specific connections and cellular properties are established during early development that are completely different from those properties seen in the mature system. In fact, this early circuitry must be "deconstructed" during postnatal development prior to completion of the final visual circuit. Starburst amacrine cells have unique properties during development and play an important (but poorly understood) role in the signals generated by this early system.  
  
<b><i>Spiking Properties</i></b>
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===Spiking Properties===
  
 
The canonical neuron transmits information through the generation of action potentials. In the retina, however, many cell types including SACs do not generate action potentials. Rather, graded depolarization is sufficient to transmit information and only the output cells of the retinal circuit create action potentials. During development, however, several of these normally non-spiking cell types do generate action potentials. Starburst amacrine cells transition late in development from a spiking to a non-spiking state, and this transition has been shown to occur though a loss of voltage-gated sodium channels.<ref name="spiking">Zhou, Z.J. & Fain, G.L. (1996). Starburst amacrine cells change from spiking to nonspiking neurons during retinal development. Proceedings of the National Academy of Sciences of the United States of America 93, 8057–8062.</ref>  
 
The canonical neuron transmits information through the generation of action potentials. In the retina, however, many cell types including SACs do not generate action potentials. Rather, graded depolarization is sufficient to transmit information and only the output cells of the retinal circuit create action potentials. During development, however, several of these normally non-spiking cell types do generate action potentials. Starburst amacrine cells transition late in development from a spiking to a non-spiking state, and this transition has been shown to occur though a loss of voltage-gated sodium channels.<ref name="spiking">Zhou, Z.J. & Fain, G.L. (1996). Starburst amacrine cells change from spiking to nonspiking neurons during retinal development. Proceedings of the National Academy of Sciences of the United States of America 93, 8057–8062.</ref>  
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The figure above shows the generation of action potentials by starburst amacrine cells in the early retina. Note that as development increases (left) the spiking of the SACs is completely abolished.  
 
The figure above shows the generation of action potentials by starburst amacrine cells in the early retina. Note that as development increases (left) the spiking of the SACs is completely abolished.  
  
<b><i>Acetylcholine</i></b>
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===Acetylcholine===
  
 
In the mature retina, SACs are not themselves responsive to acetylcholine. Rather, synapses between SACs in the mature retina are GABA-dependent and only the specific targets of SACs (i.e. direction selective ganglion cells) contain acetylcholine receptors. In the early retina, however, many cells contain nicotinic acetylchole receptors (nAChR) and are therefore responsive to ACh. Even starburst amacrine cells themselves are responsive to ACh.<ref name="dev"></ref>  
 
In the mature retina, SACs are not themselves responsive to acetylcholine. Rather, synapses between SACs in the mature retina are GABA-dependent and only the specific targets of SACs (i.e. direction selective ganglion cells) contain acetylcholine receptors. In the early retina, however, many cells contain nicotinic acetylchole receptors (nAChR) and are therefore responsive to ACh. Even starburst amacrine cells themselves are responsive to ACh.<ref name="dev"></ref>  
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Furthermore, the mechanism of transmission of ACh is dramatically different. In this early circuit, true synapses have yet to form. The transmission of ACh occurs in what is called a "volume" fashion, where a large amount of ACh is released by a cell and diffuses large distances without a specific "postsynaptic" target.<ref name="dev"></ref> Since many cells in the early retina contain AChR, spontaneous activity of a SAC can therefore activate a large number of cells.  
 
Furthermore, the mechanism of transmission of ACh is dramatically different. In this early circuit, true synapses have yet to form. The transmission of ACh occurs in what is called a "volume" fashion, where a large amount of ACh is released by a cell and diffuses large distances without a specific "postsynaptic" target.<ref name="dev"></ref> Since many cells in the early retina contain AChR, spontaneous activity of a SAC can therefore activate a large number of cells.  
  
<b><i>Retinal Waves</i></b>
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===Retinal Waves===
  
 
There are several interesting features of neuronal activity in the retina. First, it is spontaneously generated. This was first shown to occur in ganglion cells, and was then demonstrated to occur in starburst amacrine cells as well.<ref name="waves">Feller, M.B., Wellis, D.P., Stellwagen, D., Werblin, F.S. & Shatz, C.J. (1996). Requirement for cholinergic synaptic transmission in the propagation of spontaneous retinal waves. Science 272, 1182–1187.</ref> Spontaneously generated signals have been shown to be important in generating proper connectivity in various parts of the central nervous system. The second interesting fact is that, in the retina, these spontaneous signals do not propagate across the entire retina but rather are restricted to non-intersecting, dynamic "domains." A group of cells in the retina will periodically fire in a way that resembles a propagating "wave" across a portion of the retina. Over time, if you record from the entire retina, you can see that a "mosaic" pattern emerges where the retina is segregated into a variety of such domains. There also appears to be a period, perhaps of inhibition, following a given wave before another can be generated in the same region.  
 
There are several interesting features of neuronal activity in the retina. First, it is spontaneously generated. This was first shown to occur in ganglion cells, and was then demonstrated to occur in starburst amacrine cells as well.<ref name="waves">Feller, M.B., Wellis, D.P., Stellwagen, D., Werblin, F.S. & Shatz, C.J. (1996). Requirement for cholinergic synaptic transmission in the propagation of spontaneous retinal waves. Science 272, 1182–1187.</ref> Spontaneously generated signals have been shown to be important in generating proper connectivity in various parts of the central nervous system. The second interesting fact is that, in the retina, these spontaneous signals do not propagate across the entire retina but rather are restricted to non-intersecting, dynamic "domains." A group of cells in the retina will periodically fire in a way that resembles a propagating "wave" across a portion of the retina. Over time, if you record from the entire retina, you can see that a "mosaic" pattern emerges where the retina is segregated into a variety of such domains. There also appears to be a period, perhaps of inhibition, following a given wave before another can be generated in the same region.  
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Mosaic of retinal waves: In the above figure, each color represents a particular "domain" of activation.<ref name="waves"></ref> Note that, as time progresses, the domains remain spatially segregated but their locations shift.
 
Mosaic of retinal waves: In the above figure, each color represents a particular "domain" of activation.<ref name="waves"></ref> Note that, as time progresses, the domains remain spatially segregated but their locations shift.
  
<b><i>Developmental Stages</i></b>
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===Developmental Stages===
  
 
It turns out that there is not one, but three separate developmental circuits that form in the retina. As discussed above, a cholinergic network forms in the immature retina that is important in the generation of retinal waves. However, there is a stage before this in which retinal waves are generated by gap junctions (or thought to be) and a stage following it in which retinal waves are facilitated by glutamatergic connections.<ref name="dev"></ref>  
 
It turns out that there is not one, but three separat