CELLULAR NEUROSCIENCE | NEURONAL SIGNALING | CARDIOVASCULAR RESEARCH | METABOLISM | LIPID SIGNALING AND HOMEOSTASIS | ENDOCRINOLOGY | CELLULAR PHYSIOLOGY | TARGETED GENE-EXPRESSION ANALYSIS | MEMBRANE BIOLOGY | TELOMERE RESEARCH
Pirta Hotulainen, Ph.D., Docent, Head
Enni Bertling, Ph.D.
Rimante Minkeviciene, Ph.D.
Iryna Hlushchenko, M.Sc.
Amr Abou Elezz, M.Sc.
Pushpa Khanal, M.Sc.
A typical neuron possesses a cell body, dendrites, and an axon. The axon initial segment (AIS) is the site of action potential initiation. The signal sent by an axon is transmitted onto dendrites via synapses. On dendrites, most excitatory synapses are located in small protrusions called dendritic spines. Precise control of the dendritic spine morphology and density as well as the length and location of AIS is critical for normal brain function. Accordingly, both aberrant spine morphology and non-functional AIS is linked to many neurological diseases. Actin cytoskeleton is a structural element underlying proper morphology of dendritic spines and proper structure of the AIS.
Goal: We are aiming at a comprehensive model of the regulation of the actin cytoskeleton in dendritic spines and the axon initial segment during neuronal development as well as in neurological diseases. So far we have elucidated the molecular mechanisms underlying dendritic spine initiation (Saarikangas et al., Dev. Cell 2015), dendritic filopodia elongation (Hotulainen et al., JCB 2009), spine head growth (Hotulainen et al., JCB 2009) and spine head maintenance (Koskinen et al., MCN 2014). Our current working model is presented in Figure.
Figure. Working model.
Current Projects: In our current projects, we are revealing the roles of actin regulating proteins Rif and gelsolin in neurons. In addition, we study novel mechanisms to regulate the neuronal actin cytoskeleton (actin tyrosine phosphorylation and pH-dependent actin regulation). Furthermore, we elucidate the effects of genetic mutations linked to schizophrenia and autism spectrum disorder on dendritic spine density and morphology. Finally, we are clarifying the special actin regulation underlying the structure of the axon initial segment.
- Role of Rif in the brain.
- Function of gelsolin in dendritic spines.
- Phosphorylation of actin in dendritic spines.
- pH-dependent regulation of the actin cytoskeleton in dendritic spines.
- Synaptic pathology in schizophrenia and autism spectrum disorder – focus on the actin cytoskeleton.
- Regulation of the axon initial segment actin cytoskeleton.
Methods: We are taking a bottom-up approach, where molecular mechanisms learnt in simpler in vitro systems, such as test tubes, fibroblasts or dissociated hippocampal neurons, are taken to more complex systems, such as acute brain slices and the in vivo brain. At all levels, advanced microscopy techniques play a major role.
Impact: Dendritic spine density and morphology are altered in various neurological diseases. The actin cytoskeleton is a structural component regulating dendritic spine density and morphology. Manipulation of the dendritic spine actin cytoskeleton provides a means to change dendritic spine morphology and density. Thus, manipulating the actin cytoskeleton could be used to rescue the altered dendritic spine density and morphology in neurological diseases.
See also lab home page: www.helsinki.fi/neurosci/hotulainenlab/
Saarikangas, J. and Hotulainen, P. The initiation of post-synaptic protrusions. Communicative & Integrative Biology, In Press.
Abou Elezz, A., Minkeviciene, R. and Hotulainen P. Invited book chapter for a book called “Dendrites: Development and Disease”. Our chapter is under Basic biology of dendrites with the title: Cytoskeletal organization – actin. In Press.
Saarikangas, J., Kourdougli, N., Senju, Y., Chazal, G., Segerstråle M., Kuurne, J., Minkeviciene, R., Mattila, P.K., Garrett, L., Hölter, S.M., Becker, L., Racz, I., Hans, W., Klopstock, T., Wurst, W., Zimmer, A., Fuchs, H., Gailus-Durner, V., Hrabě de Angelis, M., von Ossowski, L., Taira, T., Lappalainen, P., Rivera, C. and Hotulainen, P. (2015) MIM-induced membrane bending promotes dendritic spine initiation. Dev. Cell. 33, 644–659.
Llano, O., Smirnov, S., Golubtsov, A., Soni, S., Hotulainen, P., Medina, I., Nothwang, H-G., Rivera, C. and Ludwig, A. KCC2 regulates actin dynamics in dendritic spines via interaction with βPIX. J. Cell Biol. 209, 671-686.
Koskinen, M. and Hotulainen, P. (2014) Measuring F-actin properties in dendritic spines. Front. Neuroanat. 8, 74.
Koskinen, M., Bertling E., Hotulainen, R., Tanhuanpää, K. and Hotulainen, P. Myosin IIb controls actin dynamics underlying the dendritic spine maturation. Mol. Cell. Neurosci. 61C, 56-64.
Koskinen, M., Bertling E., and Hotulainen, P. (2012) Methods to measure actin treadmilling rate in dendritic spines. Meth. Enzym. 505, 47-58.
Bertling E., Ludwig, A., Koskinen, M., and Hotulainen, P. (2012) Methods for three-dimensional analysis of dendritic spine dynamics. Meth. Enzym. 506, 391-406.
Hotulainen, P., and Hoogenraad, C.C. (2010) Actin in dendritic spines: connecting dynamics to function. J. Cell Biol. 189, 619-629.
Hotulainen, P., Llano, O., Smirnov, S., Tanhuanpää, K., Faix, J., Rivera, C., Lappalainen, P. (2009) Defining mechanisms of actin polymerization and depolymerization during dendritic spine morphogenesis. J. Cell Biol. 185, 323-339.