Tropomyosin Tpm3.1 Is Required to Maintain the Structure and Function of the Axon Initial Segment

Amr Abouelezz; Holly Stefen; Mikael Segerstråle; David Micinski; Rimante Minkeviciene; Lauri Lahti; Edna C Hardeman; Peter W Gunning; Casper C Hoogenraad; Tomi Taira; Thomas Fath; Pirta Hotulainen

doi:10.1016/j.isci.2020.101053

Tropomyosin Tpm3.1 Is Required to Maintain the Structure and Function of the Axon Initial Segment

iScience. 2020 May 22;23(5):101053. doi: 10.1016/j.isci.2020.101053. Epub 2020 Apr 12.

Authors

Affiliations

¹ Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, 00290 Helsinki, Finland; HiLIFE - Neuroscience Center, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.
² School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia.
³ Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 1, 00790 Helsinki, Finland.
⁴ Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, 00290 Helsinki, Finland.
⁵ Department of Computer Science, Aalto University School of Science, Espoo, Finland.
⁶ Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584CH Utrecht, the Netherlands.
⁷ Faculty of Veterinary Medicine, University of Helsinki, Agnes Sjöbergin katu 2, 00790 Helsinki, Finland.
⁸ School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia; Dementia Research Centre, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
⁹ Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, 00290 Helsinki, Finland. Electronic address: pirta.hotulainen@helsinki.fi.

Abstract

The axon initial segment (AIS) is the site of action potential initiation and serves as a cargo transport filter and diffusion barrier that helps maintain neuronal polarity. The AIS actin cytoskeleton comprises actin patches and periodic sub-membranous actin rings. We demonstrate that tropomyosin isoform Tpm3.1 co-localizes with actin patches and that the inhibition of Tpm3.1 led to a reduction in the density of actin patches. Furthermore, Tpm3.1 showed a periodic distribution similar to sub-membranous actin rings but Tpm3.1 was only partially congruent with sub-membranous actin rings. Nevertheless, the inhibition of Tpm3.1 affected the uniformity of the periodicity of actin rings. Furthermore, Tpm3.1 inhibition led to reduced accumulation of AIS structural and functional proteins, disruption in sorting somatodendritic and axonal proteins, and a reduction in firing frequency. These results show that Tpm3.1 is necessary for the structural and functional maintenance of the AIS.

Keywords: Biological Sciences; Cell Biology; Cellular Neuroscience; Molecular Neuroscience.