Electrophysiology of Natural and Artificial Vision - Artificial Sight: Basic Research, Biomedical Engineering, and Clinical Advances - page 365

Identifying Response Origins -
Pharmacological Dissection
In the moments after light reaches the photoreceptors, a pattern of activity propa-
gates through the neural network of the retina, from cell to cell, primarily by
chemical synapses. The pharmacology of synaptic transmission in the retina is
orderly yet complex (recently reviewed by Yang [15] ). There are just two
principle transmitters found here: glutamate and -aminobutyric acid (GABA).
Glutamate is excitatory, and GABA is (mostly) inhibitory. Glutamate mediates
information flow primarily in a vertical direction, from photoreceptors to bipolar
cells to ganglion cells. GABA mediates information primarily in lateral direc-
tions, or as upstream feedback, and is released by horizontal and amacrine cells.
Different cell types express variations of the glutamate and GABA receptors,
with the first distinction being ionotropic (ion channels, e.g. iGluRs and GABA A )
and metabotropic (coupled to G-proteins, e.g. mGluRs and GABA B ) types. There
are further subtypes of iGluRs and mGluRs, and a distinct GABA C receptor.
The various subtypes of glutamate receptors are generally named for the agonist
they are sensitive to. An agonist mimics the action of glutamate, whereas an
antagonist binds to the receptor but does not elicit the response associated
with glutamate. So, for example, the glutamate agonist N-methyl- d -aspartate
(NMDA) binds to a subset of iGluRs known as NMDA channels. Not all agonists
are highly selective, and L-aspartic acid (aspartate), a glutamate agonist, binds
readily to all glutamate receptors in the retina. In the presence of aspartate, the
rods and cones respond to light, but none of the post-synaptic neurons are able
to respond to the light-induced change in transmitter release from the photore-
ceptors. Thus, any ERG response recorded in the presence of aspartate can be
attributed to activity of the photoreceptors alone, without contributions from other
cell types.
A great deal of work has been done to identify the various receptor subtypes
expressed by the different types of retinal neurons. Indeed, the functional
subclasses of retinal neurons are defined by the receptor types they express
(though subclasses can also usually be distinguished based on morphological
differences). The point to make here is that the various agonists and antagonists
for receptor subtypes can be used to suppress the activity of subpopulations of
retinal neurons. Thus the complex response of the retina can be “dissected” by
judicious removal of cell types from the retinal network [16, 17]. The typical
protocol is to introduce the drug into the eye at an appropriate concentration
such that it binds to the appropriate receptor at a saturating level (i.e. binding
to all available receptors). In the case of an agonist, the cells so bound become
maximally depolarized (or hyperpolarized), and do not change from this state
following a light stimulus. Thus the contribution of this subpopulation of neurons
is removed from the recorded response (recall that physiological signals are
generally recorded with AC amplifiers, and the static field potential generated
by a constant membrane potential is filtered out; only changes in membrane
potential contribute to the recorded response).