Project Details
Description
Project Summary
Studies have examined retinal function using the electroretinogram (ERG) as a non-invasive method that has
the potential to mirror brain dysfunction in disease. The retina, which develops from the same tissue as the brain,
can provide a “window” into abnormal brain function. Thus, non-invasive measurements of retinal function have
garnered interest for their potential to diagnose and predict those at risk of developing neuropsychiatric diseases.
However, understanding how sex differences play a role in normal and diseased retinal function have been
understudied. This lack of knowledge limits proper interpretation and analysis of results in neurological diseases
conditions where sex differences are well established. We examined the flash ERG (fERG) in a mouse model of
schizophrenia with a mutation in serine racemase (SRKO), resulting in hypofunction of the N-methyl-D-aspartate
receptor (NMDAR). Based on sex differences in onset and severity of schizophrenia in human males versus
females, we analyzed our data based on sex and genotype. To our surprise, almost all the differences in the
fERG between these genotypes were due to the male SRKO mice. The males showed decreased amplitudes
and delayed implicit times in the a- and b-waves, while SRKO females were mainly unaffected. This male-
dominated reduction of the fERG response of SRKO mice is important in light of known differences in onset and
severity in human males with schizophrenia compared to females. While we observed sex differences in SRKO
mice, we also observed sex differences in the fERG between male and female wildtype (WT) mice. These results
suggest that sex hormones play a role in normal retinal function, but it is unclear how gonadal hormones alter
the field-potentials that drive the fERG. Interestingly, the sex differences in the mouse studies were only observed
during mesopic-light adaptation, rather than the traditional scotopic and photopic adaptation. This suggests that
sex differences in the retinal network are dominated by both rods and cones, rather than by just one type of
photoreceptor. The basis for these sex differences at the level of the retina is unknown, but if known, could be
used to leverage the use of fERG in disease conditions that differ depending on sex. We will determine if
ovarectomy or castration will eliminate the sex differences in the fERG. It is also possible that the presence of
gonadal hormones from birth may have masculinized or feminized the retina and brain during the normal period
of sexual differentiation. To test this hypothesis, we will treat neonatal male mice with flutamide (an anti-
androgen) or neonatal female mice with testosterone and determine if the sex differences in the fERG are
abolished by this early treatment that prevents sexual differentiation, which in turn alters brain development. Our
working hypothesis is that gonadal hormones play a critical role in sex differences in retinal function.
Status | Finished |
---|---|
Effective start/end date | 4/1/22 → 3/31/24 |
Funding
- National Eye Institute: $193,750.00
- National Eye Institute: $232,500.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.