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Plasticity of neuronal compartments and organelles
Neurons are highly polarized cells with well-defined subcompartments characterized by distinct structural and functional features. The most salient neuronal compartments are comprised of the somatodendritic, axonal and synaptic domains. Our work is mainly focused on further understanding the structural plasticity of the axon. Specifically, we explore the molecular composition and structural plasticity of the axon initial segment (AIS).
The AIS corresponds to the first segment of the axon and plays a crucial role since it represents the primary trigger zone for action potentials. Recently, a surprisingly high degree of AIS plasticity was revealed: Both the molecular composition as well as length and position of the AIS are dynamically regulated possibly contributing to homeostatic regulation of neuronal excitability. In this context, our ongoing studies are aimed at understanding the molecular basis as well as the functional relevance of structural AIS plasticity in the developing nervous system. Neurons also require sophisticated mechanisms facilitating correct directional transport of organelles. In this context, our second line of research is aimed at deciphering the role of interorganellar membrane contact sites for directional transport and metabolism of peroxisomes (PO) and the endoplasmic reticulum (ER) in neurons.
Fields of interest
- Neuronal polarity
- Axonal plasticity
- Interorganellar membrane contact sites
- Role of peroxisomes in neurodegeneration
Recent studies showed that structure and function of the AIS can be dynamically regulated. We hypothesized that the AIS shows a dynamic regulation during maturation of the visual cortex. A tri-phasic time course of AIS length remodeling during development was observed. To test if such dynamic maturation of the AIS is influenced by eye opening (onset of activity), animals were deprived of visual input. Such visual deprivation prevented transient shortening of the AIS maintaining a rather immature status of the AIS. These results are the first to suggest a dynamic activity-dependent maturation of the AIS in cortical neurons and point to novel mechanisms in the development of neuronal excitability.
Interorganellar membrane contact sites between PO and the ER are known to form tight structural associations. Such contact sites most likely are crucial for a diverse number of physiological processes including neuronal transport, lipid metabolism and phospholipid exchange. Most recently, we succeeded in identifying the PO membrane protein, acyl-CoA binding protein 5 (ACBD5) as a binding partner for the resident ER protein vesicle-associated membrane protein-associated protein–B (VAPB). This reveals the first molecular mechanism for establishing PO-ER associations in mammalian cells.
The Institute of Neuroanatomy will have its main focus on
- studying the role of AIS plasticity for development of the visual cortex
- uncovering the structural dynamics and functional relevance of AIS plasticity in the somatosensory cortex
- investigating structural and functional AIS heterogeneity in cortical neurons
- developing animal models for time-lapse imaging of the AIS
- studying the relevance of acyl-CoA binding protein 5 (ACBD5) for establishing PO-ER associations in vivo
- studying the role of peroxisomes for age-related neurodegeneration of the mammalian retina
Selection of recent publications
- Costello JL, Castro IG, Hacker C, Schrader TA, Metz J, Zeuschner D, Sadeghi A, Godinho LF, Costina V, Findeisen P, Manner A, Islinger M* and Schrader M* (2016) ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER. J. Cell Biol. in press (* shared senior authorship)
- Kubler J, Kirschner S, Hartmann L, Welzel G, Engelhardt M, Herskind C, et al. The HIV-derived protein Vpr52-96 has anti-glioma activity in vitro and in vivo. Oncotarget. 2016.
- Thome C, Kelly T, Yanez A, Schultz C, Engelhardt M, Cambridge SB, et al. Axon-carrying dendrites convey privileged synaptic input in hippocampal neurons. Neuron. 2014;83(6):1418-30.
- Schultz C, Engelhardt M. Anatomy of the hippocampal formation. Front Neurol Neurosci. 2014;34:6-17.
- Gutzmann A, Ergul N, Grossmann R, Schultz C, Wahle P, Engelhardt M. A period of structural plasticity at the axon initial segment in developing visual cortex. Front Neuroanat. 2014;8:11.
- Hirth M, Rukwied R, Gromann A, Turnquist B, Weinkauf B, Francke K, et al. Nerve growth factor induces sensitization of nociceptors without evidence for increased intraepidermal nerve fiber density. Pain. 2013;154(11):2500-11.
- Engelhardt M, Vorwald S, Sobotzik JM, Bennett V, Schultz C. Ankyrin-B structurally defines terminal microdomains of peripheral somatosensory axons. Brain Struct Funct. 2013;218(4):1005-16.
- Sobotzik JM, Sie JM, Politi C, Del Turco D, Bennett V, Deller T, et al. AnkyrinG is required to maintain axo-dendritic polarity in vivo. Proc Natl Acad Sci U S A. 2009;106(41):17564-9.
- Bockhart V, Constantin CE, Haussler A, Wijnvoord N, Kanngiesser M, Myrczek T, et al. Inhibitor kappaB Kinase beta deficiency in primary nociceptive neurons increases TRP channel sensitivity. J Neurosci. 2009;29(41):12919-29.
- Custer SK, Garden GA, Gill N, Rueb U, Libby RT, Schultz C, et al. Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport. Nat Neurosci. 2006;9(10):1302-11.