SUMMARY Throughout the CNS, interactions between pre- and postsynaptic adhesion molecules establish normal synaptic structure and function. Leucine-rich repeat (LRR) domain-containing proteins are a large family that has a diversity of ligands, and their absence can cause disease. At the first retinal synapse, the absence of LRIT3 expression leads to the disassembly of the postsynaptic glutamate signaling complex (signalplex) expressed on depolarizing bipolar cell (DBC) dendrites. The prevalent view is that assembly of the signalplex results from direct post-synaptic protein:protein interactions. In contrast, we demonstrate that LRIT3 is expressed presynaptically, in rod photoreceptors (rods), and when we restore LRIT3 expression in Lrit3 −/− rods, we restore expression of the postsynaptic glutamate signalplex and rod-driven vision. Our results demonstrate that, in the retina, the LRR-containing protein LRIT3 acts as a transsynaptic organizer of the postsynaptic complex required for normal synaptic function.
The aim of this study is to measure the on- and off-responses and their response asymmetries elicited by sawtooth stimuli in normal subjects and glaucoma patients. Furthermore, the correlation between the ERGs and other functional and structural parameters are investigated. Full-field stimuli were produced using a Ganzfeld bowl with Light Emitting Diodes (LEDs) as light sources. On- and off-response ERGs were recorded from 17 healthy subjects, 12 pre-perimetric and 15 perimetric glaucoma patients using 4-Hz luminance rapid-on and rapid-off sawtooth stimuli (white light; mean luminance 55 cd/m(2)) at 100% contrast. The on- and off-responses were added to study response asymmetries. In addition, flash ERGs were elicited by red stimuli (200 cd/m(2)) on a blue background (10 cd/m(2)). The mean deviations (MD) of the visual field defects were obtained by standard automated perimetry. The retinal nerve fibre layer thickness (RNFLT) was measured with Spectral Domain Optical Coherence Tomography (SOCT). We studied the correlation between ERG response amplitudes, visual field mean deviation (MDs) and RNFLT values. The on-responses showed an initial negative (N-on) followed by a positive (P-on), a late positive (LP-on) and a late negative responses (LN-on). The off-responses showed an initial positive (P-off) a late positive (LP-off) and a late negative response (LN-off). The addition of on- and off-responses revealed an initial positive (P-add) and a late negative response (LN-add). The on-response components (N-on, P-on and LN-on) in the glaucoma patients were relatively similar to those of the control subjects. However, the LP-on was significantly elevated (p = 0.03) in perimetric patients. The LP-off was significantly elevated (p < 0.001), and the amplitude of LN-off was significantly reduced in perimetric patients (p = 0.02). The LN-add amplitude was significantly reduced (p < 0.001) and delayed (p = 0.03) in perimetric patients. The amplitudes of the LN-off and LN-add ERG components were significantly correlated with the PhNR in the flash ERG (LN-off: p = 0.01; LN-add: p < 0.001) and with RNFLT (LN-off: p = 0.006; LN-add: p = 0.001). On- and off-response ERGs and their response asymmetries, elicited by sawtooth stimuli, are altered in the glaucoma patients. The late components are affected. Changes in the late negative components are correlated with structural and other functional changes.
We studied the spatial arrangement of L- and M-cone driven electroretinograms (ERGs) reflecting the activity of magno- and parvocellular pathways. L- and M-cone isolating sine wave stimuli were created with a four primary LED stimulator using triple silent substitution paradigms. Temporal frequencies were 8 and 12 Hz, to reflect cone opponent activity, and 30, 36 and 48 Hz to reflect luminance activity. The responses were measured for full-field stimuli and for different circular and annular stimuli. The ERG data confirm the presence of two different mechanisms at intermediate and high temporal frequencies. The responses measured at high temporal frequencies strongly depended upon spatial stimulus configuration. In the full-field conditions, the L-cone driven responses were substantially larger than the full-field M-cone driven responses and also than the L-cone driven responses with smaller stimuli. The M-cone driven responses at full-field and with 70° diameter stimuli displayed similar amplitudes. The L- and M-cone driven responses measured at 8 and 12 Hz were of similar amplitude and approximately in counter-phase. The amplitudes were constant for most stimulus configurations. The results indicate that, when the ERG reflects luminance activity, it is positively correlated with stimulus size. Beyond 35° retinal eccentricity, the retina mainly contains L-cones. Small stimuli are sufficient to obtain maximal ERGs at low temporal frequencies where the ERGs are also sensitive to cone-opponent processing.
Recent studies suggest a diagnostic value of the photopic negative response (PhNR) with a long-duration stimulus. The aim of this study was to record the on and off responses of the photopic fullfield electroretinogram (ERG) in normal subjects and glaucoma patients. We focused on different waves of the responses after onset and offset of the long-duration stimulus ERG. Photopic fullfield ERGs were recorded in response to a white bright LED flash on a white 20 cd/m(2) background. Stimulus luminances were 40, 60 and 80 cd/m(2). Responses were averaged using a flash duration of 240 ms and an offset period of 500 ms. We examined 19 healthy subjects, 27 patients with glaucomatous optic disc atrophy and 7 ocular hypertensive patients. The amplitudes and implicit times of the on and off responses of the human ERG depended on flash luminance. Comparing patients with glaucoma and healthy subjects for the 60 cd/m² flash, there was a significant change in the PhNRs (at onset: P < 0.01, at offset: P < 0.001) of the d-wave and of the i-wave at offset (P < 0.01). No significant difference was found for peak times of the fullfield ERG and for a- and b-wave amplitudes. PhNR amplitudes were significantly correlated with mean thickness of retinal nerve fibre layer as measured with OCT. In comparison with the normal photopic long-flash ERG, glaucoma patients showed changes in the PhNR amplitude following stimulus onset and in waves following stimulus offset.
Congenital nystagmus, involuntary oscillating small eye movements, is commonly thought to originate from aberrant interactions between brainstem nuclei and foveal cortical pathways. Here, we investigated whether nystagmus associated with congenital stationary night blindness (CSNB) results from primary deficits in the retina. We found that CSNB patients as well as an animal model (nob mice), both of which lacked functional nyctalopin protein (NYX, nyx) in ON bipolar cells (BCs) at their synapse with photoreceptors, showed oscillating eye movements at a frequency of 4–7 Hz. nob ON direction-selective ganglion cells (DSGCs), which detect global motion and project to the accessory optic system (AOS), oscillated with the same frequency as their eyes. In the dark, individual ganglion cells (GCs) oscillated asynchronously, but their oscillations became synchronized by light stimulation. Likewise, both patient and nob mice oscillating eye movements were only present in the light when contrast was present. Retinal pharmacological and genetic manipulations that blocked nob GC oscillations also eliminated their oscillating eye movements, and retinal pharmacological manipulations that reduced the oscillation frequency of nob GCs also reduced the oscillation frequency of their eye movements. We conclude that, in nob mice, synchronized oscillations of retinal GCs, most likely the ON-DCGCs, cause nystagmus with properties similar to those associated with CSNB in humans. These results show that the nob mouse is the first animal model for a form of congenital nystagmus, paving the way for development of therapeutic strategies.
Electroretinographic responses to cone and rod isolating stimuli and to simultaneous L- and M-cone modulation were measured at different temporal frequencies between 2 and 60 Hz and at two mean luminances using a four primary stimulator. The responses driven by each photoreceptor type had distinct characteristics. The responses to stimuli containing L- and/or M-cone stimulation indicated the presence of two underlying mechanisms that were active in distinct frequency regions. Between 2 and 12 Hz, the responses displayed properties that were reminiscent of the L-M-cone opponent system. At higher temporal frequencies, the electroretinograms were more determined by the luminance content in the stimuli.
Full-field electroretinograms were recorded from five normal human subjects using white light (mean luminance: 250 cd/m2) sine wave stimuli at different frequencies and contrasts. In agreement with previous studies, we found that the amplitude of the fundamental component displayed a dip at about 12 Hz, coinciding with a maximum in the second harmonic component, indicating frequency doubling of the responses. By including measurements at different contrasts, we were able to recognize two (sine-like and transient) response components. We found that the waveform of the transient response was relatively frequency independent. An algorithm to separate the two components was developed. The interaction between these two components can explain the frequency-doubled responses around 12 Hz. The sine-like component is more linear and prominent in the low-frequency region, whereas the transient seems to be more nonlinear and prominent in the high-frequency region.
The first retinal synapse, photoreceptor¡bipolar cell (BC), is both anatomically and functionally complex. Within the same synaptic region, a change in presynaptic glutamate release is sensed by both ON BCs (DBCs) via the metabotropic glutamate receptor 6 (mGluR6), and OFF BCs (HBCs) via ionotropic glutamate receptors to establish parallel signaling pathways that preferentially encode light increments (ON) or decrements (OFF), respectively. The synaptic structural organization of ON and OFF-type BCs at the photoreceptor terminal differs. DBCs make an invaginating synapse that contains a diverse but incompletely understood complex of interacting proteins (signalplex). HBCs make primarily flat contacts that contain an apparent different set of proteins that is equally uncharacterized. LRIT3 is a synaptic protein known to be essential for ON pathway visual function. In both male and female mice, we demonstrate that LRIT3 interacts with and is required for expression of nyctalopin, and thus TRPM1 at all DBC dendritic tips, but DBC signalplex components are not required for LRIT3 expression. Using whole-cell and multielectrode array (MEA) electrophysiology and glutamate imaging, we demonstrate that the loss of LRIT3 impacts both ON and OFF signaling pathway function. Without LRIT3, excitatory input to type 1 BCs is reduced, as are the visually evoked responses of many OFF retinal ganglion cells (RGCs). We conclude that the absence of LRIT3 expression disrupts excitatory input to OFF BCs and, thus disrupts the normal function of OFF RGCs.
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