Early progression in neurodegenerative disease involves challenges to homeostatic processes, including those controlling axonal excitability and dendritic organization. In glaucoma, the leading cause of irreversible blindness, stress from intraocular pressure (IOP) causes degeneration of retinal ganglion cells (RGC) and their axons which comprise the optic nerve. Previously, we discovered that early progression induces axogenic, voltage-gated enhanced excitability of RGCs, even as dendritic complexity in the retina reduces. Here, we investigate a possible contribution of the transient receptor potential vanilloid type 1 (TRPV1) channel to enhanced excitability, given its role in modulating excitation in other neural systems. We find that genetic deletion of Trpv1 (Trpv1−/−) influences excitability differently for RGCs firing continuously to light onset (αON-Sustained) vs. light offset (αOFF-Sustained). Deletion drives excitability in opposing directions so that Trpv1−/− RGC responses with elevated IOP equalize to that of wild-type (WT) RGCs without elevated IOP. Depolarizing current injections in the absence of light-driven presynaptic excitation to directly modulate voltage-gated channels mirrored these changes, while inhibiting voltage-gated sodium channels and isolating retinal excitatory postsynaptic currents abolished both the differences in light-driven activity between WT and Trpv1−/− RGCs and changes in response due to IOP elevation. Together, these results support a voltage-dependent, axogenic influence of Trpv1−/− with elevated IOP. Finally, Trpv1−/− slowed the loss of dendritic complexity with elevated IOP, opposite its effect on axon degeneration, supporting the idea that axonal and dendritic degeneration follows distinctive programs even at the level of membrane excitability.

Astrocytes are intimately involved in the response to neurodegenerative stress and have become an attractive target for the development of neuroprotective therapies. However, studies often focus on astrocytes as single-cell units. Astrocytes are densely interconnected by gap junctions that are composed primarily of the protein connexin-43 (Cx43) and can function as a broader network of cells. Such networks contribute to a number of important processes, including metabolite distribution and extracellular ionic buffering, and are likely to play an important role in the progression of neurodegenerative disease. This review will focus on the pro-degenerative and pro-survival influence of astrocyte Cx43 in disease progression, with a focus on the roles of gap junctions and hemichannels in the spread of degenerative stress. Finally, we will highlight the specific evidence for targeting these networks in the treatment of glaucomatous neurodegeneration and other optic neuropathies.

Neuronal type-specific physiologic heterogeneity can be driven by both extrinsic and intrinsic mechanisms. In retinal ganglion cells (RGCs), which carry visual information from the retina to central targets, evidence suggests intrinsic properties shaping action potential (AP) generation significantly impact the responses of RGCs to visual stimuli. Here, we explored how differences in intrinsic excitability further distinguish two RCG types with distinct presynaptic circuits, alpha ON-sustained (αON-S) cells and alpha OFF-sustained (αOFF-S) cells. We found that αOFF-S RGCs are more excitable to modest depolarizing currents than αON-S RGCs but excitability plateaued earlier as depolarization increased (i.e., depolarization block). In addition to differences in depolarization block sensitivity, the two cell types also produced distinct AP shapes with increasing stimulation. αOFF-S AP width and variability increased with depolarization magnitude, which correlated with the onset of depolarization block, while αON-S AP width and variability remained stable. We then tested if differences in depolarization block observed in αON-S and αOFF-S RGCs were due to sensitivity to extracellular potassium. We found αOFF-S RGCs more sensitive to increased extracellular potassium concentration, which shifted αON-S RGC excitability to that of αOFF-S cells under baseline potassium conditions. Finally, we investigated the influence of the axon initial segment (AIS) dimensions on RGC spiking. We found that the relationship between AIS length and evoked spike rate varied not only by cell type, but also by the strength of stimulation, suggesting AIS structure alone cannot fully explain the observed differences RGC excitability. Thus, sensitivity to extracellular potassium contributes to differences in intrinsic excitability, a key factor that shapes how RGCs encode visual information.