Abstract:
The retina employs a large number of cell types that fulfill a broad spectrum of
computations. It comes as no surprise that this complex network would make use of
an equal diversity of molecular tools, such as voltage-gated calcium channels (VGCC).
In fact, all pore-forming α1 subunits of VGCC and modulatory β and auxiliary α2δ
subunits were found in the retina. Yet, little detail is known about the functional
implementation of individual VGCC subunits in the retinal circuitry.
My work described in part 1 focused on the retinal expression and function of one
VGCC subunit, called α2δ-3, employing an α2δ-3 knockout mouse. I found transcription
of all α2δ subunit genes throughout postnatal retinal development and strong
expression of α2δ-3 in horizontal cells. Yet, in my patch-clamp recordings from isolated
horizontal cells I did not find an impact on their somatic calcium currents, leaving a
possible involvement of α2δ-3 in the horizontal cell axon-to-rod connection. Outer retina
function, determined by electroretinogram, and optokinetic reflex behavior was normal
in α2δ-3 knockout animals. However, I discovered changes to the retinal output in
micro-electrode array recordings of ganglion cell responses. I applied a paradigm of
light stimulation at different ambient luminance levels that revealed effects of the α2δ-3
knockout only in scotopic and mesopic light levels. In summary, α2δ-3 is a candidate
for horizontal cell axon-specific calcium signal modulation and exerts its function in
non-photopic regimes.
The retina constantly adapts to features of the current visual environment, most
prominently, the ambient light intensity or luminance. These adaptations are based on
mechanisms throughout the retinal network. Adaption is commonly considered to keep
signal processing within the dynamic range of the system as well as keep the retinal
output stable across changing conditions, such as the light intensity. The results of
part 1 show that different building blocks of retinal circuits - here the α2δ-3 subunit -
can contribute to retinal function at distinct light level regimes.
In part 2, we looked more generally at the output of the retina (responses of ganglion
cells) across different levels of ambient luminance. We found that ganglion cell
responses were not stable across luminance levels, neither in single ganglion cell types
nor in the ganglion cell population, but that they changed their responses qualitatively.
These response changes were also reflected downstream in the activity of the lateral
geniculate nucleus.
Furthermore, we observed that rod photoreceptors could drive visual responses of
ganglion cells in photopic luminance levels, where they were commonly thought to be
saturated. While experiencing initial incremental saturation upon stepping to photopic
luminance, rods recovered responsiveness at all light levels tested, but the rate of
recovery was faster with brighter ambient light intensity. Computational modeling
suggested adaptive translocation of elements of the signal transduction cascade as
potential explanations for rod signaling at high light intensities. The photopic rod activity
dynamics have important implications for the interpretation of experimental data and
for the question of rod photoreceptor contributions to daylight vision.
In summary, while some circuitry elements associated with luminance regimes are
known (e.g. rod and cone pathways), details on the underlying molecular mechanisms
are scarce. My data suggests α2δ-3 as a promising candidate for a molecular
determinant of light adaptation that could exert its function within horizontal cells in an
axonal compartment-specific way. It will be interesting to pinpoint the exact role of α2δ-
3 in retinal light adaptation and to determine what (sub-)cellular function this protein
serves in horizontal cells.
horizontal cells
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