Vestibulo-ocular pathways modulate extraocular muscle myosin expression patterns.

The genetic and epigenetic influences that establish and maintain the unique phenotype of the extraocular muscles (EOMs) are poorly understood. The vestibulo-ocular reflex (VOR) represents an important input into the EOMs, as it stabilizes eye position relative to the environment and provides a platform for function of all other eye movement systems. A role for vestibular cues in shaping EOM maturation was assessed in these studies using the ototoxic nitrile compound 3',3'-iminodipropionitrile (IDPN) to eliminate the receptor hair cells that drive the vestibulo-ocular reflex. Intraperitoneal injections of IDPN were followed by a 2-week survival period, after which myosin heavy chain (MyHC) analysis of the EOMs was performed. When IDPN was administered to juvenile rats, the proportion of eye muscle fibers expressing developmental and fast myosins was increased, while EOM-specific MyHC mRNA levels were downregulated. By contrast, IDPN treatment in adult rats affected only the proportion of fibers expressing developmental MyHC isoforms, leaving the EOM-specific MyHC mRNA unaltered. These data provide evidence that the VOR modulates EOM-specific MyHC expression in development. The lack of significant changes in EOM-specific MyHC expression in adult EOM following IDPN administration suggests that there may be a critical period during development when alterations in vestibular activity have significant and permanent consequences for the eye muscles.

Visual system maldevelopment disrupts extraocular muscle-specific myosin expression.

The genetic and epigenetic influences that are responsible for the establishment and maintenance of the unique phenotype of the extraocular muscles (EOMs) are poorly understood. A role for visual cues in shaping EOM maturation was assessed in rats by using two visual deprivation paradigms, dark rearing and monocular deprivation. Isoforms of the contractile protein myosin heavy chain (MHC) were used as an index of phenotypic change in developing and adult EOMs after these visual insults. In rats that were dark reared during the visual critical period, the proportion of EOM fibers expressing either fast or slow MHCs was decreased significantly. EOM-specific myosin was also sensitive to dark rearing during the critical period, as evidenced by a significant decrease in its mRNA in EOMs from these rats. EOM-specific MHC did not change in either dark-reared rats returned to normally illuminated conditions or in adult rats denied visual experience for a similar time period. These data suggest that there may be a critical period during development when alterations in visual activity have significant consequences for the eye muscle phenotype. In contrast to dark rearing, monocular deprivation had a minimal effect on expression of the typical myosin isoforms and no effect on EOM-specific myosin expression. Collectively, these data confirm the hypothesis that visual input to the oculomotor system during development modulates EOM-specific MHC expression.

The sparing of extraocular muscle in dystrophinopathy is lost in mice lacking utrophin and dystrophin.

The extraocular muscles are one of few skeletal muscles that are structurally and functionally intact in Duchenne muscular dystrophy. Little is known about the mechanisms responsible for differential sparing or targeting of muscle groups in neuromuscular disease. One hypothesis is that constitutive or adaptive properties of the unique extraocular muscle phenotype may underlie their protection in dystrophinopathy. We assessed the status of extraocular muscles in the mdx mouse model of muscular dystrophy. Mice showed mild pathology in accessory extraocular muscles, but no signs of pathology were evident in the principal extraocular muscles at any age. By immunoblotting, the extraocular muscles of mdx mice exhibited increased levels of a dystrophin analog, dystrophin-related protein or utrophin. These data suggest, but do not provide mechanistic evidence, that utrophin mediates eye muscle protection. To examine a potential causal relationship, knockout mouse models were used to determine whether eye muscle sparing could be reversed. Mice lacking expression of utrophin alone, like the dystrophin-deficient mdx mouse, showed no pathological alterations in extraocular muscle. However, mice deficient in both utrophin and dystrophin exhibited severe changes in both the accessory and principal extraocular muscles, with the eye muscles affected more adversely than other skeletal muscles. Selected extraocular muscle fiber types still remained spared, suggesting the operation of an alternative mechanism for muscle sparing in these fiber types. We propose that an endogenous upregulation of utrophin is mechanistic in protecting extraocular muscle in dystrophinopathy. Moreover, data lend support to the hypothesis that interventions designed to increase utrophin levels may ameliorate the pathology in other skeletal muscles in Duchenne muscular dystrophy.

The oculomotor periphery: the clinician's focus is no longer a basic science stepchild.

The study of the oculomotor periphery, the extraocular muscles and their orbital attachments, is undergoing a rapid expansion. This is an important progression for both basic and clinical communities as, for too long, the ophthalmologist has worked primarily in the periphery and the basic researcher has been occupied with study of the central components of the oculomotor system. From recent studies, it is clear that the morphology, cell and molecular biology, and genetics of the eye muscles and their corresponding motoneuron pools, and muscle attachments within the orbit are more complex than has heretofore been appreciated.

Spatial and temporal patterns of myosin heavy chain expression in developing rat extraocular muscle.

The present study describes transitions in myosin heavy chain expression in the extraocular muscles of rats between the ages of E17 and adult. The unique phenotype of the extraocular muscle is reflected in its fibre type composition, which is comprised by six distinct profiles, each defined by location (orbital versus global layer) and innervation pattern (single versus multiple terminals). During extraocular muscle myogenesis, developmental myosin heavy chains were expressed in both primary and secondary fibres from embryonic day E17 through the first postnatal week. At this time, the downregulation of developmental myosin heavy chain isoforms began in the global layer in a fibre type-specific manner, reaching completion only after the first postnatal month. By contrast, developmental isoforms were retained in the overwhelming majority of orbital layer fibres into adulthood and expressed differentially along the length of these fibres. Fast myosin heavy chain was detected pre- and postnatally in developing secondary fibres and in all of the singly innervated fibre types and one of the multiply innervated fibre types in the adult. As many as four fast isoforms were detected in maturing extraocular muscle, including the extraocular muscle-specific myosin heavy chain. Slow myosin heavy chain was expressed in primary fibres throughout development and in one of the multiply innervated fibre types in the adult. In contrast, the pure fast-twitch retractor bulbi initially expressed slow myosin heavy chain in fibres destined to switch to the fast myosin heavy chain developmental programme. Based upon spatial and temporal patterns of myosin heavy chain isoform transitions, we suggest that epigenetic influences, rather than purely myogenic stage-specific factors, are critical in determining the unique extraocular muscle phenotype.

The neuronal voltage-gated sodium channel, Scn8a, is essential for postnatal maturation of spinal, but not oculomotor, motor units.

Mice with a nontargeted transgene insertion at the motor endplate disease (med) locus (med(tg)) contain a deletion of a novel gene encoding a neuronal voltage-gated sodium channel, designated Scn8a. We characterized severe skeletal muscle atrophy beginning by Postnatal Day 10 (P10) and death by P20 in the med(tg) mouse. Denervation was functional, rather than structural, since the Scn8a mutation was not accompanied by retraction of neuromuscular contacts, motoneuron death, or decreased motoneuron soma diameter. Although pathology consistent with denervation was seen in both hindlimb and forelimb musculature, the postnatal maturation of the extraocular muscles was not altered. The onset of paralysis is likely coincident with the time that the Scn8a sodium channel normally assumes a critical role in the initiation and/or propagation of action potentials in spinal motoneurons. By contrast, the lack of consequences for extraocular muscle suggests that the Scn8a voltage-gated sodium channel may be of relatively minor importance for oculomotor motoneurons.

Extraocular muscles: basic and clinical aspects of structure and function.

Although extraocular muscle is perhaps the least understood component of the oculomotor system, these muscles represent the most common site of surgical intervention in the treatment of strabismus and other ocular motility disorders. This review synthesizes information derived from both basic and clinical studies in order to develop a better understanding of how these muscles may respond to surgical or pharmacological interventions and in disease states. In addition, a detailed knowledge of the structural and functional properties of extraocular muscle, that would allow some degree of prediction of the adaptive responses of these muscles, is vital as a basis to guide the development of new treatments for eye movement disorders.

Types and time course of the alterations induced in monkey blink movements by botulinum toxin.

The alterations induced in eyelid movement metrics subsequent to unilateral injections of botulinum toxin type A into the orbicularis oculi muscle were studied in chronic alert monkeys using the search coil technique. Botulinum toxin caused rapid paralysis of blinks in the treated eyelid. The amplitude and peak velocity of blinks generated by this eyelid remained at or below 20% of that of the fellow, untreated eyelid for 10-20 days. Blink amplitude gain increased linearly thereafter, attaining control values by 40-60 days after injection. Recovery of blink peak velocity was slower. The adaptive alterations in blink duration that were observed during the acute phase of toxin paralysis suggest that the mechanisms responsible for blink reflex plasticity may produce bilateral adjustments in eyelid function. Taken together, these data establish a quantitative data base that can be exploited in order to: (1) better understand the neural adaptive mechanisms that operate during eyelid movements and (2) allow quantitative comparisons between current treatment protocols that employ botulinum toxin and protocols that may lead to improvements in the treatment of chronic eyelid spasm (blepharospasm).

A switching regression analysis of urban population densities.

PIP: An application of the switching regression technique in the field of urban economics is presented. The technique is applied to the study of urban population density functions, which recent research has suggested are inherently discontinuous. The method of switching regression developed by Quandt is used to estimate density functions for selected U.S. urban areas. The results show that population density contours are highly irregular, and also that the model selection approach can be used to select the number of regimes in a switching model when this number is unknown^ieng

A note on sufficient conditions for negative exponential population densities.

PIP: The author presents some comments on the Mills-Muth model of urban spatial structure, which predicts that population density declines as distance to the urban center increases.^ieng