ORIGINAL RESEARCH PAPER
Interpretation of the mouse electroretinogram
Lawrence H. Pinto Æ Brandon Invergo Æ
Kazuhiro Shimomura Æ Joseph S. Takahashi Æ
John B. Troy
Received: 28 February 2007 / Revised: 1 May 2007 / Accepted: 3 May 2007 / Published online: 17 July 2007

Springer Science+Business Media B.V. 2007
Abstract The mouse electroretinogram (ERG)
consists of a complex set of signals or ‘‘waves’’
generated by multiple types of retinal cell. The
origins of these waves are reviewed briefly for the
C57BL/6J mouse. The differences in the properties of
these waves are described for 34 strains of mice and
11 F1 hybrid mice, as is the way that inter-strain
genetic polymorphisms can be exploited in order to
help pin-point the genes responsible for ERG differ-
ences. There are certain technical difficulties, some
subtle, that can arise in recording the ERG and these
are classified and illustrated in order to facilitate their
diagnosis. Forward genetic screens are described,
along with abnormal mice that have been generated
in a large screen. Several means are suggested for
determining if a mouse having an abnormal ERG is a
mutant.
Keywords Mouse
Inheritance
Retina

Genotype
Strain variation
Albino
Degeneration

C57BL/6J
Forward genetics
Genetic transmission
Abbreviations
ERG Electroretinogram
OP Oscillatory potential
RPE Retinal pigment epithelium
STR Scotopic threshold response
Introduction
Although long recognized as the experimental mam-
malian genetic model system of choice, it is only
recently that the mouse has been exploited for the
study of the visual system. A plethora of functional
and behavioral studies in the last five years has finally
put to rest the incorrect notion that the mouse is not a
‘visual animal’. This article is intended for those who
wish to make use of the genetic variation available
among the inbred strains and mutants of the mouse to
study the visual system. The electroretinogram
(ERG) is a noninvasive way to evaluate the function
of specific layers or neurons of the retina that also
permits the animal to breed after being tested. The
Electronic supplementary material The online version of
this article (doi:10.1007/s10633-007-9064-y) contains
supplementary material, which is available to authorized users.
L. H. Pinto (&)
B. Invergo
K. Shimomura

J. S. Takahashi
Department of Neurobiology and Physiology and Center
for Functional Genomics, Northwestern University,
2205 Tech Drive, Evanston, IL 60208, USA
e-mail: larry-pinto@northwestern.edu
J. S. Takahashi
Howard Hughes Medical Institute, Northwestern
University, Evanston, IL 60208, USA
J. B. Troy
Department of Biomedical Engineering, Technological
Institute, Northwestern University, 2145 Sheridan Road,
Evanston, IL, USA
123
Doc Ophthalmol (2007) 115:127–136
DOI 10.1007/s10633-007-9064-y

origin of the ERG is complex and has been reviewed
extensively [1–3] but for convenience will be sum-
marized here.
The electroretinogram results from the currents
that flow within the eye as a result of the light-
induced activity of neuronal, glial and retinal pigment
epithelial cells and can be analyzed into component
‘waves’ that result from specific cells or sets of cells.
The identity of the component waves and the means
by which they are measured are explained in Fig. 1A.
Photoreceptors are the source of the negative-going
a-wave [4–8]. The polarity of this wave can be
explained in part by the fact that it results from the
cessation of a standing photocurrent that flows
constantly in the dark. Rod bipolar cells are the
source of the b-wave in the dark-adapted retina
[9–12]. The b-wave can be detected with less
luminous stimuli than the a-wave in part because
bipolar cell signals represent an amplification of the
rod signals and result from a convergence of rods
onto bipolar cells [10]. However, the b-wave is not
the most sensitive to dim stimuli. Rather, the scotopic
threshold response (STR) is the most sensitive [13].
The STR is the result of inner retinal activity, but its
precise cellular origin has not been determined. The
STR in C57BL/6J mice is biphasic [13, 2]. The
c-wave is a slow, usually positive-going signal, that
originates from two opposing sources [14–16]: the
retinal pigment epithelium and retinal glial cells. The
retinal pigment epithelial cells respond to reduced
[K+] in the interphotoreceptor space during illumina-
tion and tend to produce a positive potential while the
retinal gial cells produce the negative slow PIII
component that opposes the potential resulting from
the retinal pigment epithelium. The c-wave results
from the sum of these two processes and can
therefore have either polarity. However, in C57BL/
6J mice the polarity is usually positive. Oscillatory
potentials (OP) originate in the inner retina [17] and
are quite variable in the mouse. The OP responses are
shown in Fig. 1 but will not be considered further.
Materials and methods
Mice were obtained from the Jackson Laboratory or
were bred at Northwestern University. All experi-
ments were performed in accordance with the ARVO
guidelines for the use of animals in research. During
anesthesia body temperature was maintained between
36 and 37 8C.
Recordings were made using a ‘‘Frishman-Robson’’
device [13] with DTL fibers. It is key that all
preparation was done with infra-red illumination and
image converters. A minimum of 2 h prior dark
adaptation was used [18]. Alternatively, the mouse
was dark-adapted after electrode placement.
Results
Variation of the ERG among inbred strains of the
mouse
In this section the absence of the ERG that occurs in
strains that possess the rd mutation will not be
considered (see Discussion). Although the C57BL/6J
strain is generally used for physiological, genetic and
behavioral studies of vision in the mouse, other
strains are used for certain purposes. For example,
homologous recombination, which is essential for
substituting a mutant allele of a gene for the wild-
type allele, can be done best using embryonic stem
cells derived from the 129S1/SvImJ strain. In order to
map a mutation genetically it is necessary to perform
crosses with a ‘counterstrain’ that has DNA
polymorphisms but still has a relatively normal
electroretinogram. The 129S1/SvImJ strain and the
DBA strain are both useful for this purpose. Since
albinism affects vision by increasing retinal illumi-
nation through light reflected from the back of the
eye, it is also important to keep in mind that albinism
affects the ERG, and a number of inbred strains are
albino. Not surprisingly, the ERG varies among
inbred strains [19]. This can be seen in Fig. 2 in
which the scotopic ERG is shown for three of 34
inbred strains that were studied. A number of
differences are evident. First, the c-wave is more
pronounced and tends to be more positive for C57BL/
6J than for either 129S1/SvImJ or A/J. Second, the
amplitude of the a-wave, relative to that of the
b-wave, is greater for C57BL/6J than for the other
strains. Third, the time course of the b-wave in
response to bright stimuli is much more prolonged for
A/J. We have quantified the values of the various
waves of the ERG for 34 strains and 11 F1 hybrids,
and the results are contained in Supplemental Tables
I and II. The naturally-occurring variation in the ERG
128 Doc Ophthalmol (2007) 115:127–136
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among inbred strains requires that interpretation be
done with this variation in mind. For example, in the
ERG of test cross mice produced for genetic mapping
is likely to be influenced by variation in the
background genetic composition of the test cross
mice, particularly in the F2 generation.
It should be pointed out that variation in the ERG
or any other property of vision among strains can be
used to help pin-point the genes that are responsible
for the variation. The presently-used inbred labora-
tory strains used today derive from very few wild-
caught mice (and in a few cases, wild mice) and thus
Fig. 1 The components of the C57BL/6J mouse electroreti-
nogram (ERG) and how they are measured. (A) Upper traces,
the dark-adapted ERG evoked by stimui of medium to high
luminance. Middle trace, the a-wave, b-wave and c-wave are
labeled for the response to a high luminance stimulus, showing
how the amplitude of each wave was measured for this study.
Lower drawing, sketches of the approximate time-courses of
the a-, b- and c-waves in the middle trace, were they able to be
recorded in isolation. (B) The dark-adapted ERG evoked by
two very dim stimuli (0.000176 & 0.000281 cd s/m2). The
biphasic scotopic threshold response (STR) is evoked in
this strain and its amplitude is measured as shown. (C) The
light-adapted ERG. A steady adapting light sufficient to
saturate the rod pathway (0.5 cd/m2) was presented while a
flashing stimulus was applied. The luminance of the flashing
stimulus was 0.2 cd s/m2 This same stimulus evoked a larger
response with longer latency in the dark-adapted retina (see A).
(D) Oscillatory potentials (OP) contribute to the mouse ERG
and have been digitally filtered from all responses in this paper
except for that shown here. Filtering these potentials makes it
possible to focus attention on the other waves of the ERG. A
response is shown with and without OP and below the OP time
course is shown in the absence of the rest of the ERG
Doc Ophthalmol (2007) 115:127–136 129
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their genomes are mosaics of the chromosomes of
these founder mice in which the haplotype blocks are
very small (<1 Mb) [20, 21]. The genetic diversity of
the founder mice allows the DNA derived from them
to be identified by characterizing their polymor-
phisms. The polymorphisms between many standard
laboratory strains have been characterized [22] at
over 150,000 locations in the genome. These poly-
morphisms have been used to identify known genes
that affect vision. What is needed on the part of the
investigator is to measure the phenotype in each of
many strains and then apply these data to a mapping
program designed for this purpose. The program
establishes associations between the DNA segments
of each strain (from the small number of founder
mice) and the phenotype. A program for this purpose
is available on the web (http://snpster.gnf.org/cgi-bin/
snpster_ext.cgi). Thus, naturally-occurring variation
among strains of mice provides a resource for vision
researchers that can be exploited readily at the
present time.
‘‘Abnormal’’ ERGs that are commonly
encountered
The normal ERG of the C57BL/6J strain will be used
as a basis for comparison in this section.
Responses with a transient appearance
Albino strains of mice and C57BL/6J mice that have
been light-adapted both display ERG waves that
appear more transient than those of dark-adapted
C57BL/6J mice. This is shown in the first row of
Fig. 3a. The light-adapted ERG, however, has a
smaller amplitude than the ERG of most albino
strains.
Responses with inverted appearance
There can be several reasons for the appearance of
such responses, including known pathological condi-
tions [23], but in our experience only one type of
inverted appearance is heritable. In the absence of the
b-wave, the a-wave dominates in the early phase of
the ERG and creates an initial negative-going ERG.
This occurs for mutant mice in which the pathway to
the rod bipolar cell is attenuated, which occurs in the
‘‘nob’’ series of mutations that affect either nyctal-
opin, the rod photoreceptor synaptic Ca channel, or
the bipolar cell mGluR6 receptor [24–27]. Compar-
ison of the ‘‘no b-wave’’ and ‘‘inverted responses’’
records shows that in the latter the peak of the b-wave
appears inverted but that an a-wave occurs with
normal polarity early in the response. We have never
found inverted responses of this type to be heritable
(see below) and have also found that such responses
often, but not always, become normal upon retesting.
Inverted c-wave responses often, but not always, have
normal positive polarity in C57BL/6J mice when
retested.
Distorted ERG waves
We have found two principal sources for artifactual
distortion of the ERG waves. The first occurs when
excess saline is applied to the cornea and the excess
Fig. 2 Examples of inter-strain variation in the time course of
the ERG. Note that the c-wave is more prominent for the
C57BL/6J strain than for either 129S1/SvImJ or A/J. The A/J
strain is also albino, and consistent with this some stimuli
evoke more transient responses in A/J mice than in pigmented
strains. Inter-strain variability is quantified in Supplemental
Tables I and II
130 Doc Ophthalmol (2007) 115:127–136
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Fig. 3 Technical difficulties that are often encountered when
recording the ERG. (A) Top row. Transient responses are often
associated with albino animals and light-adapted retinas, but
the peak response amplitude from light-adapted retinas in
normally sighted mice is less than in albino mice. Bottom Row.
Inverted responses can either result from genuine genetic
defects such as the mutations in nyctalopin or mGluR6 (lower
left). However inverted b- and c-wave responses can also occur
for reasons related to the condition of the mouse, a situation
that can often be clarified by retesting the mouse. (B) Top row.
Excess saline in contact with metal electrodes can cause large,
unstable liquid junction potentials and poor electrical contact
can cause distortion and instability of recording. Middle row. A
mouse with advanced retinal degeneration will have no
response whatsoever (middle left, Noerg-1, note higher
amplification of trace) but the baseline of the recording will
not be as quiet as when the amplifier is not connected to the
mouse. A normal mouse that is not presented with a stimulus
(middle right) will produce a recording with a similar baseline.
Lower row. The cone or light-adapted ERG is recorded in the
presence of a steady adapting light, in this case from an LED.
However, some LEDs lose their ability to produce a steady
light after some use and in this instance the light adaptation
will be incomplete, resulting in a larger than normal cone ERG
Doc Ophthalmol (2007) 115:127–136 131
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somehow finds its way to the contact between the
DTL fiber and the metal wire with which it makes
contact. The ensuing liquid junction potential is large
and unstable and causes the baseline to shift, often
imparting large displacements to the waves. The
second source of distortion is improper placement or
poor electrical contact with the cornea. Both of these
sources of distortion can be usually be remedied by
drying the cornea, rewetting the DTL fiber, and
replacing the contact lens; this procedure is best
learned using visible light but can be done with
practice using infrared light and image converters.
Identifying a genuinely unresponsive mouse
The ERG recording will appear to have a ‘flat line’
appearance under three conditions: when the connec-
tions to the amplifier are not made, when the mouse
does not respond, and when the stimulus has been
inadvertently omitted. The first condition will result
in a recording that has noise generated by the
amplifier and will have a peak-to-peak amplitude
(in the bandwidth of 0.1–1 kHz) of only a few
microvolts. However, if either the connection is made
properly and the mouse is unresponsive or the
stimulus is inadvertently not applied, the recordings
will not be as quiet as when the connections are not
made at all. The appearance of these two cases is
shown in Fig. 3b.
Failure of light-adaptation to occur while measuring
the cone ERG
To measure the cone ERG a steady adapting light is
applied while a flashing stimulus is presented. The
adapting light is often generated by an LED, and it is
usually presumed that LEDs have very long lifetimes.
We have witnessed the partial failure of LEDs at least
five times in 4 years of screening. The failure was
subtle: flashing stimuli were normal but a steadily
applied voltage did not produce a steady light from
the LED. This gave the false impression that the cone
ERG was much larger than it would have been had it
been recorded properly. Problems of this type can be
minimized by monthly calibration of the apparatus
and re-calibration of the apparatus every time an
unexplained abnormality appears in the electroreti-
nogram.
Mice with reproducible ERG abnormalities that are
not transmitted genetically
It has not been generally appreciated that the mouse
is useful to apply the ‘forward genetic’ approach in
which genes that are important for vision are
discovered. This approach starts with random or
spontaneous mutagenesis of a gene the identity of
which is not known, proceeds with the discovery of
visually affected mutants by screening for mice with
abnormal vision, and continues with the identification
of the mutated gene and the study of the mechanism
by which the mutated gene results in abnormal vision.
This approach offers several advantages. (1) It
requires no prior knowledge of the mechanism,
components or genes involved. (2) A number of
mutant alleles can often be isolated that alter gene
function in a number of ways. (3) This approach
usually identifies point mutations, which in some
instances can be more informative than targeted null
mutations because gain-of-function and dominant
negative mutations can be isolated. (4) Finding a
single essential gene opens the door to finding other
genes in the affected pathway. (5) This approach
parallels most closely natural mutagenesis.
Forward genetics has helped to identify proteins
involved in mammalian vision. Over 80 genes that,
when mutated, result in human retinal degeneration
have been identified [28]. The following examples
show the wide variety of essential retinal genes that
have been identified using forward genetics in
mammals. The retinal degeneration (rd) mutation in
mouse occurs in a gene for the phototransduction
cascade (Pde6rd1) [29], the rdy mutation in rats
disrupts the receptor tyrosine kinase Mertk and
impairs phagocytosis of shed rod outer segments by
the retinal pigment epithelium (RPE), resulting in
degeneration of the retina [30]. The protein nyctal-
opin, essential for bipolar cell function, was identified
by cloning the nob gene [31]. Mutation of nyctalopin
eliminates the b-wave of the ERG [25] and results in
congenital stationary night blindness (CSNB) in
humans [32]. Genes have been identified that modify
the effects of deleterious mutations. The tubby (tub)
gene in the mouse, named for its effect on body
weight, also results in retinal degeneration. However,
when mice of the C57BL/6J strain bearing this
mutation are intercrossed to mice of the AKR strain,
some of the resulting homozygous mutant mice are
132 Doc Ophthalmol (2007) 115:127–136
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spared. Those mice that are spared have inherited the
AKR allele of a defined region of chromosome 2
[33], suggesting the presence of a modifying allele on
chromosome 2. A catalog of visual mutants that has
been produced by forward genetics can be found at
the web site www.Neuromice.org.
While conducting a forward genetic screen for
mice with an abnormal ERG we measured the ERG
of over 20,000 third generation offspring (G3) of
mutagenized mice and found over 70 that had an
abnormal ERG that remained abnormal upon
retesting. In order to determine if these mice
possessed a mutation we bred each one with a wild-
type C57BL/6J mouse to obtain G4F1 mice, and then
bred the G4F1 mice with one another in order to
obtain G5F2 mice. One-fourth of these mice would
be expected to be homozygous for the mutation, so in
order to have over 80% certainty of identifying one
such homozygote we tested 20 G5F2 mice [34]. In
most cases no G5F2 mice were identified that had the
same abnormal ERG phenotype seen in the founder
affected G3 mouse. There are several explanations
Fig. 4 Responses of G3
founders in a forward
genetic screen that had
reproducibly abnormal
ERG responses. None of at
least 20 G5F2 offspring of
each of these mice were
affected. It is possible that
these mice either had a
disease or injury that was
not revealed by fundoscopy
or that the abnormal ERG
resulted from mutations in
more than one gene. The
classifications that are used
in this figure are arbitrary
and are included only to call
attention to a distinguishing
feature of the abnormal
ERG. The mouse with the
large a-wave (lower left) is
one of two G3 siblings
whose a-wave amplitude
(see supplementary Tables I
and II) was more than 2 SD
greater than the mean.
Neither sibling’s phenotype
was observed in the G4F2
mice. Each of these
abnormal phenotypes was
recorded a second time (see
Supplementary Fig. 1)
Doc Ophthalmol (2007) 115:127–136 133
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for this observation. First, it is possible that in some
cases more than one gene was mutated in the founder
G3 and thus fewer than one-fourth of the G5F2 mice
would be expected to be affected. Second, it is
possible that the retina of the founder G3 mouse was
afflicted with an injury or illness that was not
detected by fundoscopy that was performed for each
G3 mouse [18].
We have classified the ERGs of the G3 founders
that were not transmitted to G5F2 mice (‘‘non-
transmitted phenotypes’’) into nine categories
(Fig. 4). With the exception of the ‘large a-wave’
phenotype several examples of each non-transmitted
phenotype were encountered. In order to be sure that
technical problems were not responsible for the
abnormal ERG that was measured, each of the G3
founder mice were re-tested. The results of the
original test, repeat test, and G5F2 mouse ERG are
shown for each of these nine categories in Supple-
mental Figs. 1A and 1B.
Discussion
There are three principal reasons why the ERG
recorded from a mouse might differ from what the
experimenter expects from a ‘normal’ mouse. (1) The
strain background of the mouse might differ from that
of the ‘normal’ mouse that the experimenter has in
mind. Inter-strain differences in the ERG (Fig. 2,
supplemental Fig. 1 supplemental Tables I and II) are
a possible cause that needs to be considered. (2)
Technical difficulties associated with inadvertent
light-adaptation, electrode placement and stimulus
and adapting lights are a second possibility, but
careful examination of the waveform of the dark-
adapted ERG in these instances (Fig. 3) might be
helpful in arriving at a diagnosis. (3) It is possible that
a mouse with an abnormal ERG, confirmed by
retesting to eliminate technical difficulties as the
culprit, has a mutation that is responsible for the
phenotype. However, it is also possible that the
mouse has either a multi-gene defect or an illness or
injury that is not detectable by the investigator. Only
by breeding for two generations and testing 20 or
more second generation progeny can the latter
possibility be examined further.
The mouse has not, until recently, been considered
to be a ‘‘visual animal’’, and this incorrect notion
needs to be addressed. One reason that this belief was
held is that the retinal degeneration (rd, now
Pde6brd1) mutation of the phosphodiesterase 6b
enzyme occurs in many common laboratory strains
and renders all of the mice in these strains incapable
of normal responses to light [35]. Keeler, found the
retinas of some mice to be deficient in photoreceptors
[36]. This mutation was named rodless (r) and the
mutant mice were distributed to many laboratories. A
similar phenotype was found by Bru¨ckner in 1951
among wild mice from the Basel and Zurich areas
that were probably interbred with some laboratory
strains [37]; this mutation was named retinal degen-
eration (rd). The similarity between the phenotypes
of the r/r and rd/rd mutants led to speculation that
they might be the same mutation. This question was
resolved in Baehr’s laboratory by using PCR to
amplify DNA from archival microscope slides con-
taining the r/r mutant retinas [38]. The result was that
both r/r and rd/rd retinas, the latter from many
strains, contain not only the same missense mutation
but also the same polymorphisms (differences in one
or more nucleotide that usually do not result in
deleterious effects but can be used to ‘fingerprint’ the
DNA to determine its origin). This led to the
conclusion that the mutations are genetically identical
and support the interpretation that the retinal degen-
eration mutation present in many laboratory strains
has its origin in Keeler’s rodless mutation. Since so
many strains are affected with the same blinding
mutation, it is understandable that researchers would
have dismissed the mouse as a model for visual
studies beyond studies of degeneration.
In addition to the strains that carry the rd mutation,
some strains of mice bear mutations in genes other
than Pde6b that affect vision, strengthening the
impression that the mouse is not a visual animal.
For example, many laboratory strains are albino
(Tyrc) or hypopigmented, so that under the bright
illumination of a research laboratory, they may not be
able to see properly. The fact that a number of
common laboratory strains have genetic alterations
impairing their vision does not mean, of course, that
the majority of strains of mice without these muta-
tions are also blind. However, it has undoubtedly
contributed to the perception that all mice are blind or
have poor vision.
Mice, of course, are not blind. C57BL/6J mice
perform well in a number of behavioral tasks [39, 40]
134 Doc Ophthalmol (2007) 115:127–136
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and their ERG is very similar to that of other
mammals that are generally considered to be ‘‘visual
animals’’. It is hoped that the results presented in this
paper will allow researchers to exploit the genetic
variation of the mouse to better understand the visual
system, using the ERG as a tool for studying the early
steps of vision that occur in the retina.
Acknowledgement The faculty and students at the Jackson
Laboratory Workshops on Mouse Vision in 2004 and 2006
contributed to the framework for this paper. This work was
supported by U01-MH61915 from the NIH.
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