Partial rescue of retinal function in chronically hypoglycemic mice.
OBJECTIVE
Mice rendered hypoglycemic by a null mutation in the glucagon receptor gene Gcgr display late-onset retinal degeneration and loss of retinal sensitivity. Acute hyperglycemia induced by dextrose ingestion does not restore their retinal function, which is consistent with irreversible loss of vision. The goal of this study was to establish whether long-term administration of high dietary glucose rescues retinal function and circuit connectivity in aged Gcgr-/- mice.


METHODS
Gcgr-/- mice were administered a carbohydrate-rich diet starting at 12 months of age. After 1 month of treatment, retinal function and structure were evaluated using electroretinographic (ERG) recordings and immunohistochemistry.


RESULTS
Treatment with a carbohydrate-rich diet raised blood glucose levels and improved retinal function in Gcgr-/- mice. Blood glucose increased from moderate hypoglycemia to euglycemic levels, whereas ERG b-wave sensitivity improved approximately 10-fold. Because the b-wave reflects the electrical activity of second-order cells, we examined for changes in rod-to-bipolar cell synapses. Gcgr-/- retinas have 20% fewer synaptic pairings than Gcgr+/- retinas. Remarkably, most of the lost synapses were located farthest from the bipolar cell body, near the distal boundary of the outer plexiform layer (OPL), suggesting that apical synapses are most vulnerable to chronic hypoglycemia. Although treatment with the carbohydrate-rich diet restored retinal function, it did not restore these synaptic contacts.


CONCLUSIONS
Prolonged exposure to diet-induced euglycemia improves retinal function but does not reestablish synaptic contacts lost by chronic hypoglycemia. These results suggest that retinal neurons have a homeostatic mechanism that integrates energetic status over prolonged periods of time and allows them to recover functionality despite synaptic loss.
Center for Vision Research and SUNY Eye Institute, Department of Ophthalmology, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
Yumiko
Y
Umino
Nicolas
N
Cuenca
Drew
D
Everhart
Laura
L
Fernandez-Sanchez
Robert B
RB
Barlow
Eduardo
E
Solessio
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002908:Chronic Disease; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D007003:Hypoglycemia / Q000178:diet therapy / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012160:Retina / Q000378:metabolism / Q000503:physiopathology*; D012162:Retinal Degeneration / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D012165:Retinal Ganglion Cells / Q000502:physiology*
D001786:Blood Glucose; D004040:Dietary Carbohydrates