Download Neurotransmitters in the retina

Neurotransmitters in the retina
1. General characteristics.
Today's research on the retina focuses a great deal of attention on
neurotransmission between the neurons of the retina. New techniques using
autoradiography, immunology and molecular biology are developing
specific stains for neurochemicals, their synthesizing enzymes or the nucleic
acids manufacturing these chemicals, so that cells containing these
compounds can be marked. Cells stained with horseradish peroxidase
conjugated antibodies to the neurotransmitters are particular spectacular
because they are stained to their finest dendrites and so can be readily
classified with their Golgi-stained equivalents. Furthermore, the whole
population of neurotransmitter specific neurons is stained so one can
understand their topographical organization into mosaics across the entire
retina. Some immunocytochemistry for the common neurotransmitter
candidates has been performed on the human retina but more has been done
in the monkey retina and so far the findings are the same in general. The
consistency of cell types staining across species boundaries, in mammals at
least, suggest that most, with a few exceptions, of the neurotransmitters,
neuromodulators and neuropeptides discovered in nonhuman retinas will be
present in human retina too.
2. The neurotransmitter of neurons of the vertical pathways through the
retina is glutamate.
Glutamate is the strongest candidate for being the neurotransmitter of the
neurons of the vertical pathways through the retina. All photoreceptor types,
rods and cones, probably use the excitatory amino acid glutamate to transmit
signals to the next order neuron in the chain. There was originally some
evidence for the closely related amino acid, aspartate, being present in rods
but the latest sophisticated techniques of demonstrating amino acid
signatures in retinal neurons cannot confirm aspartate as a retinal
neurotransmitter at all. Uptake, release and action of glutamate and agonists
upon second-order neurons in slice preparations or isolated cells in tissue
culture have also all confirmed glutamate to be the neurotransmitter acting at
the first synapse in the retina. The action of the photoreceptor
neurotransmitter upon the second-order neurons is through two different
types of sensory channels though. The one type of postsynaptic receptor type
is a metabotropic glutamate channel that involves a second messenger
cascade and cyclic GMP for activation of the channel (in the ON-center
bipolar cell) whereas the other is an ionotropic channel via AMPA receptors
and Na ions (OFF-center bipolar and horizontal cell). Photoreceptors in most
vertebrates including human, have a content of D2 dopamine receptors
somewhere upon their surface .
Glutamate is also thought to be the neurotransmitter of all bipolar cells and
most ganglion cells in the vertebrate retina including the monkey retina. In
an immunocytochemical study of the human retina a similar conclusion was
drawn by us. All the ganglion cells appeared to label strongly with
antibodies to glutamate.
Bipolar cells have receptor channels that are either of the metabotropic type
(APB sensitive) or ionotropic type (AMPA) at their dendrites in the OPL,
while their axonal ending in the IPL have channels and receptors for GABA
(A, B and C types), D1 dopamine and glycine because, of course, all kinds
of amacrine cells are presynaptic at these sites in the IPL neuropil. Ganglion
cells are as diverse in receptor sensors as the bipolar cells with the addition
of receptors to acetylcholine, and the first appearance in the retina of NMDA
glutamate receptors like in the brain.
3. Gamma aminobutyric acid.
The classical inhibitory neurotransmitters, gamma aminobutyric acid
(GABA) occurs in many different varieties of amacrine cells and in one or
more classes of horizontal cell in most vertebrate retinas. There is still some
controversy over whether GABA is contained within horizontal cells in
monkey and human retina.
In this figure (Fig. 2) taken from human retina, it can be seen that there is
heavy staining with antibodies to GABA in the inner plexiform layer (three
bands are particularly obvious) and in about half of the amacrine cell bodies
in the lower row of amacrine cells in the inner nuclear layer. Some displaced
amacrines and interplexiform cells are also revealed with GABA
immunocytochemistry. However, the horizontal cells are not stained at all.
A valuable identification of individual cell types that contain GABA has
come from double staining techniques upon Golgi stained cell types. Thus
we know now that A2, A10, A13, A17, A19, and the interplexiform cell
accumulate GABA and probably use it as their primary neurotransmitter.
Some amacrine cell types also colocalize GABA with another
neurotransmitter. Thus the GABAergic A17 colocalizes serotonin, the
acetylcholine (starburst amacrine) colocalizes GABA and so does the
dopamine A18 cell. Neuropeptides are also commonly colocalized with
GABA i.e. substance P in A22 is almost certainly the secondary transmitter
to GABA as the primary. GABAergic amacrine cells and IPCs act upon
bipolar, amacrine and ganglion cell processes or cell bodies in the neuropils
of the retina via all the three varieties of GABA receptors (A, B and C types)
but the specifics of which receptors are associated with which morphological
or physiological subtype of cell, still needs elucidation.
4. Glycine.
The other classic inhibitory neurotransmitter glycine, accounts for the
remainder of the amacrine cells (those that are not GABAergic) in the
vertebrate retina . In addition one or more types of bipolar cell are also
thought to be glycinergic in mammalian retinas including monkey and
human.
In this picture it can be seen that the immunostaining for glycine is just as
strong in the inner plexiform layer as GABA staining. About the same
number of amacrine cells are revealed. However there is an addition of some
small bipolar cell bodies in the inner nuclear layer and the occasional large
cell body of a ganglion cell type in the ganglion cell layer.
Two morphological types of glycinergic amacrine cell can be demonstrated
even in immunocytochemical staining of the whole population of glycinergic
amacrines in human retina. The less intensely stained cell has the
morphological features of the rod pathway AII amacrine cell (i.e lobular
appendages and thick apical dendrite arising from a mitral shaped cell body
protruding down into the neuropil of the IPL). Pourcho and Goebel (1985)
showed quite clearly that tritiated glycine accumulated in Golgi stained AII,
A4, and A8 cells. The latter cell was the most strongly glycinergic of the
three small field amacrine cells, so we suggest that this amacrine is also
most intensely stained in the human retina.
Glycine receptors are found on all the neurons that are postsynaptic to these
glycinergic (all small-field) amacrine cells. Thus receptors are found on
certain bipolar cell axons, and on many amacrine and ganglion cell
dendrites. Again like for the GABA receptors, linking receptor type to
morphological type of postsynaptic cell is still a hot topic for research in the
retina.
5. Acetylcholine.
The classic fast excitatory neurotransmitter of the peripheral nervous system,
acetylcholine (ACh), is found in a mirror symmetric pair of amacrine cells in
the vertebrate retina. In the rabbit such cells have been named starburst cell
(Famiglieti, 1983; Masland and Tauchi, 1986). One of the mirror pair occurs
in the amacrine cell layer with dendrites in sublamina a (OFF sublamina of
the IPL). The other of the pair has its cell body displaced to the ganglion cell
layer and its dendrites stratify in sublamina b (ON sublamina of the IPL).
These ACh containing amacrine cells are common to almost all vertebrate
retinas and have been described morphologically in human retina too. Both
muscarinic and nicotinic receptors have been demonstrated in the
mammalian retina, particularly associated with transient phasic ganglion
cells (Y cells) and effects of A.Ch. and antagonists on ganglion cell
responses are documented but not well understood.
6. Serotonin.
There are two types of serotonin-accumulating amacrine cell in the rabbit
retina. One of these is almost certainly the A17 cell or the reciprocal
amacrine cell of the rod system in the rabbit. However, in cat retina, a
completely different amacrine cell type stains with antibodies against
serotonin. One cell type in cat is similar to the wide-field cell A20, while the
other may be the A18 or dopamine cell. Even where serotonin is strongly
demonstrated in these amacrine cells in rabbit retina, it is not thought to be
the neurotransmitter.
Serotonin co-exists with GABA, in the A17 cell and the latter is thought to
be the releasable transmitter. A few cold-blooded vertebrates have a
bistratified amacrine cell and a bipolar cell type that immunostain for
serotonin.