Abstract
Purpose :
Elevated eye pressure (ocular hypertension, OHT) causes optic nerve (ON) injury that leads to eventual dysfunction and degeneration of retinal ganglion cells (RGCs) in glaucoma. The goal of this study is to determine how early OHT affects the function of thalamocortical relay neurons (TC neurons) in the dorsal lateral geniculate nucleus (dLGN), a major brain nucleus receiving RGCs inputs in an experimental mouse model of OHT.
Methods :
Bilateral anterior chamber injection of 10-micron polystyrene microbeads was used to induce a modest (~30% increase) and sustained OHT in 6-8 week-old mice (control = saline injection). Eye pressure was monitored with a TonoLab tonometer and experiments were performed at 5 and 8 weeks post-injection. TC neurons were targeted for whole-cell recordings in coronal dLGN slices using a K+-based pipette solution with neurobiotin. Post-recording, TC neurons were processed with fluorescent streptavidin and dendrites were analyzed with a Sholl analysis. Optical coherence tomography (OCT) was used to measure central retinal thickness. Data are mean±SD and significance was tested using a t-test.
Results :
OHT TC cells were slightly depolarized relative to control (control: -81±5 mV, n=38; OHT: -75±3 mV, n=23; p<0.0001) and input resistance was elevated in OHT cells (Control: 328±86 MΩ; OHT: 443±91 MΩ; p<0.005). Depolarization with 500-ms current injections revealed that OHT TC cells fired more action potentials than controls (160 pA; control: 15.0±8.0; OHT: 23.6±6.2, p<0.005). This was reflected in a higher steady-state spike frequency in OHT (46±12 Hz vs 31±15 Hz in control, p<0.01). 5 weeks of OHT also led to a significant reduction in dendrite complexity. There was no detectable thinning of the inner retina measured by OCT at this time point. By 8 weeks OHT, TC neuron spiking was reduced, with TC neurons firing only 6.8±4.3 spikes (n=10). At this time point, input resistance (271±82 MΩ) and resting potential (-83.6±4.2 mV) appeared to recover to near control levels.
Conclusions :
These findings indicate that OHT alters the membrane properties and excitability of neurons receiving input from retinal ganglion cells in the visual thalamus along a biphasic time course. The mechanisms of these changes and their influence on responses to RGC synaptic inputs have yet to be determined.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.