The axon initial segment (AIS) is a specialized portion of the proximal axon that mediates the initiation and propagation of action potentials in CNS neurons. Structurally, the AIS is comprised of densely packed voltage-gated sodium (Nav) and potassium channels (Kv) that are held in place by a complex network of structural proteins and tethering molecules. Much recent evidence suggests that AISs are tailored to help optimize specific elements of neuronal function although many details of the relationship between AIS structure and neuronal spiking remain unknown. The mammalian retina is particularly attractive for this type of study because of its diverse range of well-classified ganglion cell types, each with distinct light responses, i.e., AIS properties can be correlated to spiking responses both within and across types.
Background
Previous studies have shown that neurons of the chick nucleus laminaris that are sensitive to low auditory frequencies have AISs that are shorter and further from the soma (vs. those sensitive to higher frequencies); the differences in the length and location are thought to help maximize the sensitivity to the interaural time differences (ITD) associated with each frequency range. In thick-tufted pyramidal neurons of the somatosensory cortex however, the length of the AIS does not vary systematically but instead, the distance between the AIS and the soma is inversely correlated to the size of the apical dendrite; this arrangement helps maintain consistency in the amplitude of the back-propagated action potential across a wide range of cellular morphologies. In the retina, we’ve previously shown that both the length of the AIS as well as its distance from the soma are correlated to the size of the soma as well as the overall extent of the dendritic field. In a separate study, we found that within alpha OFF-transient ganglion cells, the length of the AIS is tailored to the amount of synaptic input received by the cell: in the dorsal retina where synaptic inputs are relatively sustained, longer AISs are essential for the generation of sustained trains of spiking whereas in the ventral retina, AISs are shorter and thus limit the duration of spiking, combining with the relatively short-duration synaptic inputs they receive to ensure only transient spike bursts are transmitted to higher visual centers. These studies suggest that individual components of the AIS work together to control several different aspects of spike shape as well as the properties of the spike train. Our goal is to understand the principles by which AIS structure helps shape neuronal firing.
What we do
We study the relationship between AIS structure and function in mouse retinal ganglion cells. The mouse retina is attractive for this work as a large number of different types of ganglion cells each generate unique spiking responses to light stimuli allowing AIS properties to be correlated both within and across cell types. In addition to studying length and location of the AIS, we also evaluate its composition, e.g., the specific sub-types of voltage-gated sodium and potassium channels that comprise the AIS. We also explore the effect of disease on AIS properties.
Selected Publications
Fried SI, Lasker AC, Desai NJ, Eddington DK & Rizzo JF (2009). Axonal sodium channel bands shape the response to electric stimulation in retinal ganglion cells. J. Neurophys. Apr;101(4):1972-87. PMID: 19193771. PMCID: PMC4588392.
Jeng, J, Tang, S, Molnar, A, Desai, NJ & Fried, SI (2011). The sodium channel band shapes the response to electric stimulation in retinal ganglion cells. J Neural Eng. 2011 Jun;8(3):036022. PMID: 21558602.
Raghuram, V, Werginz, P, Fried, SI (2019), Somatodendritic and AIS scaling in retinal ganglion cells helps to regulate spike properties and maintain response consistency, Front. Cell. Neurosci, https://doi.org/10.3389/fncel.2019.00436. PMID: 31611777
Werginz, P, Raghuram, V, Fried, S.I. (2020), Tailoring of the axon initial segment underlies reliable conversion of synaptic inputs into spiking output in OFF-Alpha T retinal ganglion cells, Science Advances, 2020 Sep 11;6(37):eabb6642. doi:10.1126. PMID: 32917708.
Raghuram, V., Werginz, P., Fried, S.I., Timko, B., (2021), Morphological factors that underlie neural sensitivity to simulation in the retina, Advanced NanoBiomed Research 2021, PMID: 35399546.
