Pilot grant funding from the Center for the Molecular Biology of Neurosensory Systems COBRE.
Synaptic dysfunction in neurodegenerative diseases. One of the most obvious effects of neurodegenerative disease is the death of neurons. However, neurodegenerative diseases are also accompanied by dramatic dysfunction that occurs long before neurons die. Synapses - points of communication between neurons - are highly susceptible to dysfunction in many of these diseases and evidence arising from a both animal models and human patients indicates that the same is true of glaucoma, a blinding and irreversible neurodegenerative disease characterized by sensitivity to intraocular pressure and death of retinal ganglion cells (RGCs), the output neurons of the retina. Many elegant studies coming from several labs have pointed to specific anatomical defects at synapses in the retina in both animal models and human patients. However, the impact on retinal signaling to the brain is largely unknown. We are currently using rodent glaucoma models to probe how synaptic function is altered by elevated IOP before substantial RGC death. We accomplish this using a combination of patch-clamp electrophysiological recordings of neurons in acute brain slices, retinal slices, and whole-mount retinas, 2-photon calcium imaging, and immunohistochemistry and anatomical techniques. Understanding how synaptic transmission is altered in glaucoma will inform novel diagnostic and therapeutic strategies for detecting and treating retinal disease. Additionally, since glaucoma shares several features in common with Alzheimer’s, Parkinson’s, and ALS, exploration of the mechanisms underlying retinal dysfunction in glaucoma will yield novel insights into neuronal death and dysfunction in neurodegenerative diseases that strike beyond the visual system.
Novel explorations of retinal bipolar cell synaptic function. Prior to reaching RGCs, visual information is routed from rod and cone photoreceptors through a population of ~12 distinct classes of bipolar cells (BCs). Each BC is tuned to carry different features of the photoreceptor output, thereby giving rise to parallel processing at the earliest steps of the visual pathway. Signals diverge further as BCs make synapses onto >30 functionally-defined RGCs classes. The ability of each of these parallel information streams to encode different features of the visual scene appears to result from multiple factors along the pathway from photoreceptor phototransduction to RGC spiking. Processes regulating synaptic transmission at bipolar cell axon terminals, such as postsynaptic receptor properties, exocytosis kinetics, Ca2+ channel properties, Ca2+ buffering, and short-term plasticity, are likely major contributors. Differences in each of these can endow different synapses with specialized capabilities, making synapses not only points of information transfer, but powerful sites of information processing. A substantial body of work has examined the synaptic function of rod bipolar cells (RBCs). There is no guarantee, however, that insights from RBCs are applicable to understanding the function of other bipolar cells, especially as rod bipolar cells are adapted to signaling principally at the absolute dimmest limits of vision, where photon capture by rods is a relatively rare event. Cone bipolar cells (CBCs), in contrast, signal under both rod and cone-dominated conditions, serving as relays from AII amacrine cells in dim light conditions and carrying signals directly from cones in brighter light. Thus, CBCs process and transmit visual signals across all lighting conditions. To address this gap in our knowledge, we will use a combination of transgenic mouse lines, 2-photon calcium imaging, and patch-clamp electrophysiology to characterize the synaptic function of defined CBC classes onto known retinal ganglion cell targets. This is pursued with an eye toward understanding how CBC synaptic function gives rise to the unique response properties of the post-synaptic ganglion cells.
We are grateful for grant funding from the Bright Focus Foundation National Glaucoma Research Program!