Hotulainen Lab

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Regulation of the actin cytoskeleton in dendritic spines and the axon initial segment.

Dendritic spines are small protrusions in neuronal dendrites where the postsynaptic components of most excitatory synapses reside in the brain. Specific sets of new spines arise during new experiences or the acquisition of new skills, and provide the foundation for their retention. The actin cytoskeleton is a structural element underlying specific changes in dendritic spine morphology. The proper morphology of spines and proper regulation of the actin cytoskeleton have been shown to be important for memory and learning. Consequently, defects in the regulation of the actin cytoskeleton in neurons have been implicated in memory disorders as well as in many psychiatric diseases, such as schizophrenia and autism. The more we understand the mechanisms that regulate the structural plasticity of dendritic spines, the more we will know about the alterations in synaptic plasticity in neurological diseases.

The proximal ends of axons contain the axon initial segment (AIS). The AIS serves as the site of action potential initiation and plays a role in maintaining neuronal polarity. The clustering of sodium channels at the AIS facilitates spike generation, while its role in maintaining polarity is the result of a vesicle filter and diffusion barrier that restrict the entry of dendritic proteins and membrane lipids into the axon. The AIS is a remarkably stable structure comprising a specialized membrane and protein complex. Central to this complex is ankyrin G. We have recently shown that Tropomyosin 3.1, and thus intact actin cytoskeleton, is required for the proper maintenance of the AIS structure and function.

Goal of research: To obtain a comprehensive understanding of the regulation of the actin cytoskeleton in dendritic spines and the axon initial segment during neuronal development as well as in neurological diseases.

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.

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 or organotypic brain slices and the in vivo brain. At all levels, advanced microscopy techniques play a major role.