Increased Susceptibility to Glaucomatous Damage in Microfibril Deficient Mice

Area of Science:

• Ophthalmology
• Neuroscience
• Genetics

Background:

• Microfibrils, crucial components of connective tissue, are primarily formed by fibrillin-1.
• Defects in fibrillin-1 can lead to connective tissue disorders with ocular manifestations.
• The Tsk mutation in fibrillin-1 (Fbn1Tsk/+) causes microfibril deficiency in mice.

Purpose of the Study:

• To investigate if mice with microfibril deficiency (Fbn1Tsk/+) exhibit increased susceptibility to pressure-induced retinal ganglion cell (RGC) degeneration.
• To assess the structural and functional changes in the optic nerve following induced intraocular pressure (IOP) elevation in these mice.

Main Methods:

• Induced elevated IOP in Fbn1Tsk/+ and wild-type (wt) mice using microbead injection into the anterior chamber.
• Monitored IOP over four months.
• Quantified RGC number by staining retinas for Brn3a.
• Analyzed optic nerve structure, including nerve area, axon number, and pia mater thickness, using p-phenylene diamine staining.

Main Results:

• Fbn1Tsk/+ mice experienced significantly less IOP elevation compared to wt mice.
• Fbn1Tsk/+ mice displayed larger optic nerves and axons, with a thinner pia mater.
• Despite lower IOP, Fbn1Tsk/+ mice showed significantly greater loss of RGCs (14.8% vs. 5.8%) and optic nerve axons (17.0% vs. 7.5%) compared to wt mice.

Conclusions:

• Mice with microfibril deficiency due to the Fbn1Tsk/+ mutation have altered optic nerve structure.
• These mice exhibit increased susceptibility to optic nerve degeneration induced by elevated IOP, even with lower pressure levels.
• Microfibril integrity is critical for protecting RGCs and optic nerve axons against pressure-induced damage.