Eye alignment changes caused by sustained GDNF treatment of an extraocular muscle in infant non-human primates

Abstract

The ability of sustained treatment of a single extraocular muscle with glial cell line-derived neurotrophic factor (GDNF) to produce a strabismus in infant non-human primates was tested. Six infant non-human primates received a pellet containing GDNF, releasing 2 µg/day for 90 days, on one medial rectus muscle. Eye alignment was assessed up to 6 months. Five of the six animals showed a slow decrease in eye misalignment from the significant exotropia present at birth, ending with approximately 10° of exotropia. Controls became orthotropic. Misalignment averaged 8° three months after treatment ended. After sustained GDNF treatment, few changes were seen in mean myofiber cross-sectional areas compared to age-matched naïve controls. Neuromuscular junction number was unaltered in the medial rectus muscles, but were significantly reduced in the untreated lateral recti. Neuromuscular junctions on slow fibers became multiply innervated after this sustained GDNF treatment. Pitx2-positive cells significantly decreased in treated and contralateral medial rectus muscles. Our study suggests that balanced GDNF signaling plays a role in normal development and maintenance of orthotropia. Sustained GDNF treatment of one medial rectus muscle resulted in a measurable misalignment largely maintained 3 months after treatment ended. Structural changes suggest mechanisms for producing an imbalance in muscle function.

Alteration of Neurotrophic Factors and Innervation in Extraocular Muscles of Individuals With Concomitant Esotropia

“… 17 In a previous strabismus animal model, multiple slender nerve fibers were connected to a neuromuscular junction, and the number increased from 4.2% to 21.3% in neuromuscular junctions with more than one axon due to the effects of neurotrophic factors. 14 The findings on neurotrophic factors also indicated its involvement in trophic signaling alterations in the EOMs, 20 which can trigger a microcascade of plasticity at the muscle and motor neuron levels. 6 It has been demonstrated that continuous treatment with a neurotrophic factor has the potential to correct eye alignment in a sustained manner, which may override compensatory mechanisms in the ocular motor system.…”

“… 6 It has been demonstrated that continuous treatment with a neurotrophic factor has the potential to correct eye alignment in a sustained manner, which may override compensatory mechanisms in the ocular motor system. 14 , 18 , 21 …”

“… 13 In individuals with strabismus, GDNF was downregulated, IGF-1 expression was inconsistent, and BDNF expression was not changed. 7 In previous non-human primates studies, 14 , 15 the number of nerve fibers and the density of neuromuscular junctions can be regulated by exogenously applied GDNF, leading to eye alignment changes; however, the sustained delivery of 2 µg/day BDNF for 3 months to EOMs did not induce strabismus in infant monkeys. 16 …”

Effect of Fibroblast Growth Factor 2 on Extraocular Muscle Structure and Function

“…12,13 These neurotrophic factors have varying effects on extraocular muscle contraction properties, force generation, and relaxation rates, as well as extraocular muscle cross-sectional areas. [14][15][16][17][18][19] Sustained local administration of IGFI on extraocular muscle partially reversed eye misalignment in a nonhuman primate model of strabismus. 20 It is possible that the abrupt changes in the visual world and as well as the direct changes to muscle tension resulting from strabismus surgery or toxin administration trigger compensatory mechanisms that drive the oculomotor system back to presurgical ocular misalignment.…”