Matthew J. Gastinger

Dendrite remodeling and other abnormalities in the retinal ganglion cells of Ins2 Akita diabetic mice.

PURPOSE To determine the extent of retinal ganglion cell loss and morphologic abnormalities in surviving ganglion cells in Ins2 Akita/+ diabetic mice. METHODS Mice that expressed cyan fluorescent protein (CFP) or yellow fluorescent protein (YFP) reporter genes under the transcriptional control of the Thy1 promoter were crossed with Ins2 Akita/+ mice. After 3 months of diabetes, the number and morphology of retinal ganglion cells was analyzed by confocal microscopy. The number of CFP-positive retinal ganglion cells was quantified in retinas of Ins2(Akita/+) Thy1-CFP mice. The morphology of surviving cells was examined, and dendritic density was quantified in Ins2 Akita/+ Thy1-YFP mice by using the Sholl analysis. RESULTS Thy1-CFP expression was limited to retinal ganglion cell bodies. There was a 16.4% reduction in the density of CFP-positive ganglion cells in the peripheral retina of Ins2 Akita/+ mice compared with wild-type control retinas (P < 0.017), but no significant change in the central retina. Thy1-YFP expression occurred throughout the entire structure of a smaller number of cells, including their soma, axons, and dendrites. Six different morphologic clusters of cells were identified in the mouse retinas. The structure of dendrites of ON-type retinal ganglion cells was affected by diabetes, having 32.4% more dendritic terminals (P < 0.05), 18.6% increase in total dendrite length (P < 0.05), and 15.3% greater dendritic density compared with control retinas, measured by Scholl analysis. Abnormal swelling on somas, axons, and dendrites were noted in all subtypes of ganglion cells including those expressing melanopsin. CONCLUSIONS The data show that retinal ganglion cells are lost from the peripheral retina of mice within the first 3 months of diabetes and that the dendrites of surviving large ON-type cells undergo morphologic changes. These abnormalities may explain some of the early anomalies in visual function induced by diabetes.

Retinopetal axons in mammals: emphasis on histamine and serotonin.

Since 1892, anatomical studies have demonstrated that the retinas of mammals, including humans, receive input from the brain via axons emerging from the optic nerve. There are only a small number of these retinopetal axons, but their branches in the inner retina are very extensive. More recently, the neurons in the brain stem that give rise to these axons have been localized, and their neurotransmitters have been identified. One set of retinopetal axons arises from perikarya in the posterior hypothalamus and uses histamine, and the other arises from perikarya in the dorsal raphe and uses serotonin. These serotonergic and histaminergic neurons are not specialized to supply the retina; rather, they are a subset of the neurons that project via collaterals to many other targets in the central nervous system, as well. They are components of the ascending arousal system, firing most rapidly when the animal is awake and active. The contributions of these retinopetal axons to vision may be predicted from the known effects of serotonin and histamine on retinal neurons. There is also evidence suggesting that retinopetal axons play a role in the etiology of retinal diseases.

Histamine Receptors in Mammalian Retinas

Mammalian retinas are innervated by histaminergic axons that originate from perikarya in the posterior hypothalamus. To identify the targets of these retinopetal axons, we localized histamine receptors (HR) in monkey and rat retinas by light and electron microscopy. In monkeys, puncta containing HR3 were found at the tips of ON‐bipolar cell dendrites in cone pedicles and rod spherules, closer to the photoreceptors than the other neurotransmitter receptors. This is the first ultrastructural localization of any histamine receptor and the first direct evidence that HR3 is present on postsynaptic membranes in the central nervous system. In rat retinas, most HR1 were localized to dopaminergic amacrine cells. The differences in histamine receptor localization may reflect the differences in the activity patterns of the two species. J. Comp. Neurol. 495:658–667, 2006.

Serotonergic retinopetal axons in the monkey retina

Purpose: To describe serotonergic retinopetal axons in monkeys. Methods: Whole macaque and baboon retinas, fixed in 4% paraformaldehyde, were labeled with antisera raised against serotonin (5-HT). Results: Several large-diameter 5–HT-immunoreactive (IR) axons emerged from the optic disk. Most axons ran to the peripheral retina, where they branched extensively. Most terminated in the ganglion cell layer, but a few 5-HT-IR axons terminated in distal inner plexiform or within inner nuclear layer. Some axons branched extensively near the fovea, and a dense plexus of 5-HT-IR axons was also found around the optic disk. Varicose 5-HT-IR axons were also associated with blood vessels, especially in the central retina. Conclusions: Immunoreactive serotonin is present in a distinct population of retinopetal axons in the monkey retina. Receptors for serotonin are present in the primate retinas, and based on physiological studies in other mammals, these retinopetal axons are expected to modulate neuronal activity and regulate blood flow.

The effects of histamine on rat and monkey retinal ganglion cells.

Mammalian retinas receive input from the posterior hypothalamus, and the neurotransmitter in this pathway is histamine. To determine whether histamine influences ganglion cells, we analyzed the effects of histamine on their maintained and light-evoked activity in vitro. In monkeys, histamine increased the maintained firing rate in 42% of ganglion cells, decreased it in 38%, and had no effect in 20%. When histamine and the HR3 agonist, methylhistamine, were applied to the same cells in succession, their effects were sometimes different, a finding suggesting that at least one other histamine receptor is present. In addition, the responses of some ganglion cells to full-field light stimuli were decreased by histamine and methylhistamine. In rats, the effects of histamine were somewhat different. Histamine increased the maintained firing rate of 82% of ganglion cells. Methylhistamine and the HR2 agonist, dimaprit, had the same effects as histamine. In some cells, histamine increased the light responses, but in others it decreased them. Histamine had no effect on ganglion cells in either species when synaptic transmission was blocked by low Ca2(+)/high Mg2+ Ames medium. Thus, the major effects of histamine were on the maintained activity of retinal ganglion cells. In both rats and monkeys, 80% or more of the ganglion cells were affected by histamine, and these responses were mediated by at least two of the histamine receptor subtypes.