Andrew Ishida

Research Interests

Retinal ganglion cells generate the first pulsatile signals in the visual system that enable us to perceive and respond to viewed scenes. Ganglion cells use these signals (termed "spikes") to transmit signals to, and thereby drive higher-order processing in, multiple brain regions. Because changes in spike size, duration, and timing significantly affect signal transmission between cells in some systems, our research questioned whether ganglion cells only generate spikes or whether ganglion cells also modify and regulate spikes. Our interest was whether ganglion cell spikes are digital and memoryless, or if not, then how, when, and why spike properties are malleable in, and variable among, ganglion cells. In essence, we asked whether ganglion cells play a passive role, versus a more active role, in vision.  

Our early studies focused on how ganglion cells generate spikes – specifically, the transmembrane ionic currents that form and shape spikes. We then studied how dopamine (the major modulatory chemical released during daytime inside the eye by some amacrine and interplexiform cells) alters ganglion cell spikes, and whether these effects resemble those of transitioning from darkness to daylight. Our later studies compared intraocular spikes (in ganglion cell axons before they exit the eye to form the optic nerve) versus extraocular spikes (in the optic nerve, optic chiasm, and optic tract) because ganglion cell axons are unmyelinated inside the eye and myelinated outside the eye. We asked whether and how spikes affect the shape and propagation of subsequent spikes, and whether spikes differ in functionally different ganglion cells. 

We found that retinal ganglion cell spikes are more complex than previously known or modeled. The details include differences between cells, the kinetics of changes in ion channel states, and intracellular regulatory mechanisms. Specifically, we found that ganglion cells possess more types of ionic current than are needed to generate spikes; that ganglion cells differ in the ionic currents they use to shape spikes and spiking patterns; that some of these currents (particularly that carried by Na⁺) are diminished by spiking and then recover at multiple rates (partly fast, partly slow); that these rates are modulated in multiple ways by dopamine; that at least three enzymes (protein kinase A, protein kinase C, CaMKII) regulate ganglion cell spikes and/or ionic currents; that light alters the activity of at least two of these enzymes; and that the effect of light on the level of ganglion cell CaMKII activation differs inside and outside the eye. 

Notably, we found that activated CaMKII alters the speed at which spikes travel along axons, in a way that can help ganglion cells filter (and possibly guard against energy-demanding or deleterious effects of) high spike frequencies. Recently, we identified a K⁺ channel subunit isoform that CaMKII physically associates with in optic nerve and that, in other systems, CaMKII regulates in ways consistent with the effects of CaMKII-related reagents we found on spike propagation speed. Curiously, we found that the duration of individual spikes differs between the axons of functionally distinct ganglion cells in ways that differentially support signal transmission to target cells in multiple systems. 

CBS Graduate Group Affiliation

• Neuroscience Graduate Group