The Visual System

Müller Glia

Mark Eastburn, Marti Luby, Tzu-Ting Kao, Jonas Chiu, Jenny Choi, Shailee Patel, and Girija Chatufale
 Topic Talk Outline

History

Müller Cells

4 Homeostatic Functions
Neurotransmitter Recycling
Spatial Potassium Buffering
Water Clearance
Release of Gliotransmitters

Conclusion
 Glial Cells of the Retina

Microglia Macroglia
Primary immune cells Support cells

Defense Homeostatic + metabolic

Inflammation support for
Repair photoreceptors and
neurons

Astrocytes Müller cells

(Reichenbach & Bringmann, 2020)

Müller

History
 Evolution of Knowledge

Mid-1800s: Neurons + Glia

1950s: Detailed study of glial cells

Müller cells were one of the first

glial cells to be formally identified,
in 1851.

Unfortunately, this was during the

time that glial cells were termed the
“glue” of the nervous system.
German retinal anatomist
Heinrich Müller (1820-1864)
(Werner et al., 2021) (Fan & Agid, 2018)
 The 4 Contributions of Heinrich Müller
Some of Müller’s first
experiments involved
illuminating the eye &
examining the shadows
produced.
He concluded that light
does not pass as a
straight line through the
eye (as Purkinje & others
had previously thought).
(Werner et al., 2021)
Studying the cellular Before his time, it was The Müller cell, a radial
layers of the vertebrate thought that glial cell, was identified by
(fish) retina phototransduction began Müller in 1851.
in the ganglion cell layer.
Müller proposed that
vision, in fact, started at
the photoreceptor cells
at the back of the retina.
This was later confirmed
by Tartuferi, a student of
Camillo Golgi.
(Chvatal & Verkhratsky, 2018; Dell’Orco et al., 2021) (Dell’Orco et al., 2021; Werner et al., 2021) (Chvatal & Verkhratsky, 2018; Fan & Agid, 2018)
Müller

Müller Cells
 Müller Cells and Structure
Ganglion cell
ILM: formed by basal
lamina at the inner
retinal surface and end
foot

Müller cells are type of glial cell Müller cell

that span entire retina.

1. Müller cells span between Bipolar Cell

the inner and outer
Blood Vessel
limiting membranes.

Cone cell
OLM: formed of
müller and
photoreceptor cells

Rod cell

(Reichenbach & Bringmann, 2020) (Li et al., 2019)

 Function of Müller Cells

Müller cells play critical roles assisting:

1. Metabolic support for the retina
a. Between blood vessels and
retinal ganglion cells.
b. Regulate and transport
molecules between the
neurons and blood
circulation
c. Glucose molecules are
transported to Müller cells

Müller cells are directly responsible for

the light conduction in the retina.
In the retina, the Müller cells establish the
blood- retinal barrier.
(Reichenbach & Bringmann, 2020) (Rudraraju et al., 2020)
Müller Cells in Fovea

Fovea contains two types of Müller glia

1. Müller cell cone in foveola
2. Z-shaped MüllerCells of foveal walls.

Müller cells in fovea do not support the

activity of photoreceptors and
neurons. But they provide the stability
of the foveal tissue.

Müller cells improve the light

transmission through the tissue to
photoreceptors.

Müller cells get activated upon virtually

all pathogenic stimuli.

(Bringmann et al., 2020)

Müller

Homeostatic Functions
Neurotransmitter Recycling

Image Source: (YANG, 2004)

 Neurotransmitter Recycling

Lateral Inhibition

- Dark depolarises photoreceptors

- Depolarisation releases
neurotransmitters
- Light hyperpolarizes photoreceptors
- Hyperpolarization stops release of
neurotransmitters

- Glutamate excites horizontal cells

and OFF bipolar cells
- Glutamate inhibits ON bipolar cells
- GABA inhibits photoreceptors

Image Source: (L-Type Calcium Channel, 2022)

 Neurotransmitter Recycling

GABA Uptake Voltage Dependent processes Glutamate Uptake

(-ve potential starts/maintains uptake)
Mediated by: Mediated by:
- GABA-A receptors - Glutamate-Aspartate
- Electrogenic transport: transporter (GLAST)
➥2Na+, 1 Cl- Importance:
- Visual Resolution in
OPL
- Rapid termination of
Glutamine Synthetase synaptic activity in
Importance: IPL
- Pharmacological Hindered if:
Blockade - Muller cell is
➢Functional depolarised
blindness ➥potassium
- Downregulation ➢ conductance
Glutamate toxicity

Image Source: (BRINGMANN et al., 2006)

 Spatial Potassium Buffering
Müller cells remove excess extracellular potassium ions into
blood vessels, vitreous, and subretinal space to avoid
hyperexcitation and maintain homeostasis (Reichenbach &
https://www.moleculardevices.com/a Bringmann, 2010; Newman, Frambach, & Odette, 1984).
pplications/patch-clamp-electrophys
iology/what-action-potential

Kir4.1: inwardly and outwardly rectifying potassium

channels. They are located at perivascular, vitreal endfoot
membranes, and microvilli that extend into the subretinal
space (Kofuji et al., 2002; Nagelhus et al., 1999).

Kir2.1: inwardly rectifying potassium channels (Kofuji et al.,

2002). They are located on the membrane.

(Skatchkov et al., 2006)

 Spatial Potassium Buffering
The amplitude of the Kir currents decreases as
age increases, and the currents through L-type
(long-lasting) high voltage-activated (HVA)
calcium channels increase with age. Both
increase levels of Müller cell gliosis, a immune
response that protects but potentially damages
retinal cells as well (Bringmann et al., 2003).

(Reichenbach & Bringmann, 2020)

https://en.wikipedia.org/wiki/L-type_calcium_channel#:~:text=The%20L%2Dtype%20calcium%20channel,channel%20has%
20four%20isoforms%3A%20Cav1.
 Water Clearance

Under normal conditions, water may

accumulate in the retinal tissue:

1. Coupled transportation of glucose and

water;
2. Intraocular pressure-induced water
influx from the vitreous;
3. Metabolic water production coupled by
oxidative degradation of glucose.

The clearance of excessive water can be

performed by Müller cell by coupled
transportation of potassium and water,
facilitated by aquaporin-4 water channels.
(Reichenbach & Bringmann, 2020)
 Water Clearance

(Reichenbach & Bringmann, 2020)

Aquaporin-4 and Kir 4.1 expressed on perivascular membrane: Bidirectional potassium and
water flux across cell membrane.

Aquaporin-4 expressed on perisynaptic membrane: Restrict the paracellular water flow into
neurons.
 Gliotransmitters

● Müller cells release

glutamate (excitatory
neurotransmitter)
○ When cell is depolarized, glutamate
endocytosis is reversed and
neurotransmitter is pumped into
extracellular space
○ Calcium-dependent
neurotransmitter exocytosis via
vesicles upon activation by receptor
agonists or voltage-gated ion
channels (Na+ and Ca2+)
○ Excess glutamate release can have
excitotoxic effects on affected
neurons.
Image source: Giaume et al., 2007
Gliotransmitters

● Müller cells sensitize

ganglion and amacrine
cells by releasing D-serine,
which must bind NMDA
receptors before glutamate
can have intended effect
○ D-serine is an agonist for
glutamate
○ May be involved with
synaptogenesis of developing
eyes

Image source: Kalia et al., 2008

 Gliotransmitters
● Adenosine (inhibitory
neurotransmitter) is also
released from Müller cells.
○ Action at A3 receptors on
neurons decreases
P2X7-induced apoptosis in
ganglion cells of the retina
○ Can upregulate production of
NTPDase1, which degrades
ATP into adenosine for
neuroprotective effects

Image source: Lu et al., 2017

Müller

Conclusion
 The Paradox of Müller Glia:

Because Müller cells are found throughout the retina (and because the microglia of
the retina are in constant communication with them) virtually every pathogenic
stimulus entering the retina will induce a Müller cell reaction.

While these reactions are often neuroprotective, they can go awry and accelerate the
progress of neuronal degeneration instead.

Just how the integrity of Müller cells is compromised remains to be understood.

 Where do we go from here?

● Confirming findings from animal models in human cells

● Müller cells represent a promising target for therapeutic
interventions as they span the entire length of the retina and are
known to survive many pathogenic conditions that afflict the neural
cells of the retina

Potential therapies:
○ Adenovirus-mediated delivery of neurotrophic factors to preserve light damaged
photoreceptors
○ Reactiving the dormant neural progenitor properties of Müller cells and enabling
their differentiation into neurons and photoreceptors
 Take-Home Messages

● Müller cells provide homeostasis and metabolic support for photoreceptors

and neurons, and structural support for retinal tissue.
● Functions related to homeostasis include: neurotransmitters recycling (GABA
and Glutamate Uptake to Glutamine Synthesis), spatial potassium buffering
(Rectifying K+ channels maintain K+ levels in retina), water clearance (water
and K+ movement), and the release of gliotransmitters.
● There is still a lot to be learned about Müller cells and more research is
needed to better understand how these cells can be harnessed to rectify
diseases of the retina.
https://newsroom.tiktok.com/en-us/tiktok-q-and-a
 References
Baird-Daniel, E., Daniel, A., Wenzel, M., Li, D., Liou, J. Y., Laffont, P., Zhao, M., Yuste, R., Ma, H., & Schwartz, T. H. (2017). Glial Calcium Waves
are Triggered by Seizure Activity and Not Essential for Initiating Ictal Onset or Neurovascular Coupling. Cerebral Cortex (New
York, N.Y. : 1991), 27(6), 3318–3330. https://doi.org/10.1093/cercor/bhx072

Biedermann, B., Bringmann, A., Franze, K., Faude, F., Wiedemann, P., & Reichenbach, A. (2004). GABA(A) receptors in Müller glial cells of
the human retina. Glia, 46(3), 302–310. https://doi.org/10.1002/glia.20004

Bringmann, A., Francke, M., Pannicke, T., Biedermann, B., Faude, F., Enzmann, V., ... Reichenbach, A. (1999). Human Müller glial cells:
Altered potassium channel activity in proliferative vitreoretinopathy. Investigative Ophthalmology & Visual Science, 40(13),
3316–3323.

Bringmann, A., Kohen, L., Wolf, S., Wiedemann, P., & Reichenbach, A. (2003). Age-related decrease of potassium currents in human
retinal glial (Müller) cells. Canadian Journal of Ophthalmology, 38(6), 464–468.

Bringmann, A., Pannicke, T., Grosche, J., Francke, M., Wiedemann, P., Skatchkov, S. N., Osborne, N. N., & Reichenbach, A. (2006). Müller
cells in the healthy and diseased retina. Progress in retinal and eye research, 25(4), 397–424.
https://doi.org/10.1016/j.preteyeres.2006.05.003

Bringmann, Andreas & Grosche, Antje & Pannicke, Thomas & Reichenbach, Andreas. (2013). GABA and Glutamate Uptake and
Metabolism in Retinal Glial (Müller) Cells. Frontiers in endocrinology. 4. 48. 10.3389/fendo.2013.00048.
 References
Bringmann, A., Unterlauft, J., Wiedemann, R., Barth, T., Rehak, M., & Wiedemann, P. (2020, July 6). Two different populations of Müller
cells stabilize the structure of the fovea: an optical coherence tomography study. SpringerLink.
https://link.springer.com/article/10.1007/s10792-020-01477-3?error=cookies_not_supported&code=ac343759-2be2-4f27-814a-fcf55
f455d4b

Giaume, C., Kirchhoff, F., Matute, C., Reichenbach, A., & Verkhratsky, A. (2007, April 13). Glia: The Fulcrum of Brain Diseases. Nature News.
Retrieved April 10, 2022, from https://www.nature.com/articles/4402144

Chvátal, A., & Verkhratsky, A. (2018). An early history of neuroglial research: Personalities. Neuroglia, 1(1), 245–281.
https://doi.org/10.3390/neuroglia1010016

Dell’Orco, D., Koch, K.-W., & Rispoli, G. (2021). Where vision begins. Pflügers Archiv - European Journal of Physiology, 473(9), 1333–1337.
https://doi.org/10.1007/s00424-021-02605-3

Devoldere, J., Peynshaert, K., De Smedt, S. C., & Remaut, K. (2019). Müller cells as a target for retinal therapy. Drug Discovery Today, 24(8),
1483–1498. https://doi.org/10.1016/j.drudis.2019.01.023

Jaffe L. F. (2008). Calcium waves. Philosophical Transactions of the Royal Society of London. Series B, Biological sciences, 363(1495),
1311–1316. https://doi.org/10.1098/rstb.2007.2249

Fan, X., & Agid, Y. (2018). At the origin of the history of glia. Neuroscience, 385, 255–271. https://doi.org/10.1016/j.neuroscience.2018.05.050
 References
Gauthier, R., Joly, S., Pernet, V., Lachapelle, P., & di Polo, A. (2005). Brain-Derived Neurotrophic Factor Gene Delivery to Müller
Glia Preserves Structure and Function of Light-Damaged Photoreceptors. Investigative Ophthalmology & Visual
Science, 46(9), 3383. https://doi.org/10.1167/iovs.05-0362

Higgs, M. H., & Lukasiewicz, P. D. (1999). Glutamate uptake limits synaptic excitation of retinal ganglion cells. The Journal of
neuroscience : the official journal of the Society for Neuroscience, 19(10), 3691–3700.
https://doi.org/10.1523/JNEUROSCI.19-10-03691.1999

Kofuji, P., Biedermann, B., Siddharthan, V., Raap, M., Iandiev, I., Milenkovic, I., ... Reichenbach, A. (2002). Kir potassium channel subunit
expression in retinal glial cells: Implications for spatial potassium buffering. Glia, 39(3), 292–303.

Li, X., Liu, J., Hoh, J., & Liu, J. (2019, May 1). Müller cells in pathological retinal angiogenesis. ScienceDirect.
https://www.sciencedirect.com/science/article/pii/S1931524418302391

Lu, W., Albalawi, F., Beckel, J. M., Lim, J. C., Laties, A. M., & Mitchell, C. H. (2017). The P2X7 receptor links mechanical strain to cytokine IL-6
up-regulation and release in neurons and astrocytes. Journal of neurochemistry, 141(3), 436–448. https://doi.org/10.1111/jnc.13998

Matsui, K., Hosoi, N., & Tachibana, M. (1999). Active role of glutamate uptake in the synaptic transmission from retinal nonspiking
neurons. Journal of Neuroscience, 19(16), 6755-6766.

Nagelhus, E. A., Horio, Y., Inanobe, A., Fujita, A., Haug, F. M., Nielsen, S., ... Ottersen, O. P. (1999). Immunogold evidence suggests that
coupling of K+ siphoning and water transport in rat retinal Müller cells is medi- ated by a coenrichment of Kir4.1 and AQP4 in
specific membrane domains. Glia, 26(1), 47–54.
 References
Newman, E. A., Frambach, D. A., & Odette, L. L. (1984). Control of extra- cellular potassium levels by retinal glial cell K+ siphoning. Science,
225 (4667), 1174–1175.

Newman, E. A. (1985). Membrane physiology of retinal glial (Muller) cells. The Journal of Neuroscience, 5(8), 2225–2239.
https://doi.org/10.1523/jneurosci.05-08-02225.1985

Pannicke, T., Fischer, W., Biedermann, B., Schädlich, H., Grosche, J., Faude, F., ... & Reichenbach, A. (2000). P2X7 receptors in Müller glial
cells from the human retina. Journal of Neuroscience, 20(16), 5965-5972.

Pérez-Cerdá, F., Sánchez-Gómez, M. V., & Matute, C. (2015). Pío del Río Hortega and the discovery of the oligodendrocytes. Frontiers in
Neuroanatomy, 9. https://doi.org/10.3389/fnana.2015.00092

Pow, D. V., & Robinson, S. R. (1994). Glutamate in some retinal neurons is derived solely from glia. Neuroscience, 60(2), 355–366.
https://doi.org/10.1016/0306-4522(94)90249-6

Rauen, T., Taylor, W. R., Kuhlbrodt, K., & Wiessner, M. (1998). High-affinity glutamate transporters in the rat retina: a major role of the glial
glutamate transporter GLAST-1 in transmitter clearance. Cell and tissue research, 291(1), 19–31.
https://doi.org/10.1007/s004410050976

Rudraraju, M., Narayanan, S. P., & Somanatha, P. (2020, November 1). Regulation of blood-retinal barrier cell-junctions in diabetic
retinopathy. ScienceDirect. https://www.sciencedirect.com/science/article/pii/S1043661820314237
 References
Reichenbach, A., & Bringmann, A. (2010). Müller cells in the healthy and diseased Retina. Springer.

Reichenbach, A., & Bringmann, A. (2020). Glia of the human retina. Glia, 68(4), 768–796. https://doi.org/10.1002/glia.23727

Skatchkov, S. N., Eaton, M. J., Shuba, Y. M., Kucheryavykh, Y. V., Derst, C., Veh, R. W., Wurm, A., Iandiev, I.,
Pannicke, T., Bringmann, A., & Reichenbach, A. (2006). Tandem-pore domain potassium channels are
functionally expressed in retinal (Müller) glial cells. Glia, 53(3), 266–276.
https://doi.org/10.1002/glia.20280

The role of retinal muller cells in retinal function and retinal damage - Prof. Ido erlman. (2017, June 4). [Video]. YouTube.
https://www.youtube.com/watch?v=EhFGt3kCSxk

Visual System (sensory System) Part 2. (n.d.). What-When-How.com.

http://what-when-how.com/neuroscience/visual-system-sensory-system-part-2/

Warren, N. J., Tawhai, M. H., & Crampin, E. J. (2010). Mathematical modelling of calcium wave propagation in mammalian airway
epithelium: evidence for regenerative ATP release. Experimental physiology, 95(1), 232–249.
https://doi.org/10.1113/expphysiol.2009.049585

Werner, J. S., Gorczynska, I., & Spillmann, L. (2021). Heinrich Müller (1820-1864) and the entoptic discovery of the site in the retina where
vision is initiated. Journal of the History of the Neurosciences, 31(1), 64–90. https://doi.org/10.1080/0964704x.2021.1959165

Yang, X. (2004). Characterization of receptors for glutamate and GABA in retinal neurons. Progress in Neurobiology, 73, 127-150.
https://www.moleculardevices.com/applications/patch-clamp-electrophysiology/what-action-potential
 References
Ye, S. S., Tang, Y., & Song, J. T. (2021). ATP and Adenosine in the Retina and Retinal Diseases. Frontiers in Pharmacology, 12, 654445.
https://doi.org/10.3389/fphar.2021.654445

L-type calcium channel. (2022, March 23). Wikipedia.

https://en.wikipedia.org/wiki/L-type_calcium_channel#:~:text=The%20L%2Dtype%20calcium%20channel