Modulation of narrow-field amacrine cells on light-evoked spike responses and receptive fields of retinal ganglion cells.

By using multi-electrode array (MEA) recording technique in conjunction with white-noise checkerboard stimuli and reverse correlation methods, we studied modulatory actions of glycinergic narrow-field amacrine cells (NFACs) on spatiotemporal profiles of five functional groups of ganglion cells (GCs) in dark-adapted mouse retinas. We found that application of 2 µM strychnine significantly altered light-evoked spike rates of three groups of GCs. It also decreased receptive field center radii of all five groups of GC by a mean value of 11%, and shifted the GC receptive field (RF) centers of all GCs and the mean shift distances for the sustained GCs are significantly longer than the transient GCs. On the other hand, strychnine did not affect temporal profiles of the GC center responses, as it did not alter the time-to-peak or the biphasic index of the spike triggered average (STA) functions of GC RF centers. Strychnine also exerts limited actions on RF surrounds of most GCs, except that it moderately weakens the antagonistic surround of sustained OFF GCs and strengthens the antagonistic surround of the ON/OFF GCs, possibly through serial connections between NFACs and GABAergic wide-field amacrine cells (WFACs). Using the Sum of Separable Subfilter (SoSS) model and singular value decomposition method, we decomposed GCs' STAs into five space-time separable subfilters, studied the observation rates of each subfilter in the five functional groups of GCs and determined NFAC-dependent and -independent synaptic circuitries that mediate center and surround responses of various groups of mouse retina retinal ganglion cells.

Glycinergic and GABAergic interneurons shift the location and differentially alter the size of ganglion cell receptive field centers in the mammalian retina.

By using the multi-electrode array (MEA) recording technique in conjunction with white-noise checkerboard stimuli and reverse correlation methods, we studied modulatory actions of glycinergic and GABAergic interneurons on spatiotemporal profiles of ganglion cells (GCs) in dark-adapted mouse retinas. We found that application of 2 µM strychnine decreased receptive field center radii of GCs by a mean value of 11%, and shifted the GC receptive field (RF) centers by a mean distance of 28.3 µm. On the other hand, 200 µM picrotoxin + 100 µM bicuculline + 50 µM TPMPA increased GC receptive field center radii by a mean value of 19%, and shifted the GC RF centers by a mean distance of 53.7 µm. Glycinergic neurons in the mouse retina are narrow-field amacrine cells that have been shown to mediate ON-OFF crossover inhibitory synapses within the RGs' RF center, therefore they may increase the size and shift the location of GC RF center by synergistic addition to bipolar cell inputs to GCs. GABAergic neurons are wide-field amacrine cells and horizontal cells that are known to mediate antagonistic surround responses of GCs, and thus they decrease the GCs' RF center size. Our results suggest that a major global function of glycinergic and GABAergic interneurons in the mammalian retina is to provide the flexibility for adjusting the size and location of GCs' RF centers. The apparent shifts of GC RF centers suggest that the synergistic addition by GlyACs and the surround inhibition by GABAergic interneurons are not spatially symmetrical within GC RFs.

Genetic dissection of rod and cone pathways mediating light responses and receptive fields of ganglion cells in the mouse retina.

Retinal ganglion cells (GCs) are important visual neurons which carry complex spatiotemporal information from the retina to higher visual centers in the brain. By taking advantage of pathway-specific knockout/mutant mice and multi-electrode array (MEA) recording techniques, we analyze contributions of rod and cone pathways to responsiveness, kinetics and receptive field profiles of GCs under scotopic and photopic conditions. Our data suggest: (1) Scotopic responses of some GCs require all three rod pathways, some require only the secondary and tertiary rod pathways, and others require only the tertiary rod pathway. (2) There are more responsive GCs in photopic conditions than responsive GCs in scotopic conditions. (3) Gap junctions slow down GCs' scotopic light responses and increase GCs' ratio of antagonistic to center inputs. (4) Cone pathways do not affect the kinetics but alter the ratio of antagonistic to center inputs of scotopic GC responses, and they speed up GCs photopic responses and alter the ratio of GCs' antagonistic to center synaptic inputs and receptive field profiles. (5) Rod bipolar cells shorten response latency of ON GCs and increase the ratio of GCs' antagonistic to center synaptic inputs. (6) Light adaptation speeds up GCs' temporal processing and tunes GC photopic responses to higher frequencies, and the tertiary rod pathway plays a significant role in adaptation-induced TTP changes in some GCs. (7) GC RF center sizes are partially mediated by AIIACs and GC-GC coupling. (8) Connexin36 gap junctions and cone pathways alter synaptic circuits underlying antagonistic surround inputs to GCs in photopic conditions.

Elevated IOP alters the space-time profiles in the center and surround of both ON and OFF RGCs in mouse.

Glaucoma is a leading cause of blindness worldwide, and is characterized by progressive retinal ganglion cell (RGC) death. An experimental model of glaucoma has been established by elevating the intraocular pressure (IOP) via microbead occlusion of ocular fluid outflow in mice. Studies in this model have found visual dysfunction that varied with adaptational state, occurred before anatomical changes, and affected OFF RGCs more than ON RGCs. These results indicate subtle alterations in the underlying retinal circuitry that could help identify disease before irreversible RGC changes. Therefore, we looked at how RGC function was altered with elevated IOP under both photopic and scotopic conditions. We first found that responses to light offset are diminished with IOP elevation along with a concomitant decrease in receptive field center size for OFF RGCs. In addition, the antagonistic surround strength and size was reduced in ON RGCs. Furthermore, elevation of IOP significantly accelerated the photopic temporal tuning of RGC center responses in both ON and OFF RGCs. We found that some of the IOP-induced functional changes to OFF RGCs relied on ON cross-over pathways, indicating dysfunction in inner retinal circuitry. Overall, these results suggest that IOP alters multiple functions in the retina depending on the adaptational state. They provide a basis for designing multiple functional tests for early detection of glaucoma and for circuit-specific therapeutic targets in treatment of this blinding disease.