Hotulainen Lab

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Rimante Minkeviciene

We have performed a comprehensive behavioral and anatomical analysis of the missing in metastasis (Mtss1/MIM) knockout (KO) mouse brain.

MIM-Induced Membrane Bending Promotes Dendritic Spine Initiation
Saarikangas J, Kourdougli N, Senju Y,Chazal G, Segerstrale M, Minkeviciene R, Kuurne J, Mattila PK, Garrett L, Holter SM, Becker L, Racz I, Hans W, Klopstock T, Wurst W, Zimmer A, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, von Ossowski L, Taira T, Lappalainen P, Rivera C and Hotulainen P (2015)
MIM-Deficient Mice Exhibit Anatomical Changes in Dendritic Spines, Cortex Volume and Brain Ventricles, and Functional Changes in Motor Coordination and Learning
Minkeviciene R, Hlushchenko I, Virenque A, Lahti L, Khanal P, Rauramaa T, Koistinen A, Leinonen V, Noe FM and Hotulainen P (2019)

We also analyzed the expression of MIM in different brain regions at different ages. MIM is an I-BAR-containing membrane-curving protein, shown to be involved in dendritic spine initiation and dendritic branching in Purkinje cells in the cerebellum. Behavioral analysis of MIM KO mice revealed defects in both learning and reverse-learning, alterations in anxiety levels and reduced dominant behavior, and confirmed deficiency in motor coordination and pre-pulse inhibition. Anatomically, we observed enlarged brain ventricles and decreased cortical volume. Although MIM expression was relatively low in the hippocampus after early development, hippocampal pyramidal neurons exhibited reduced density of thin and stubby dendritic spines. Learning deficiencies can be connected to all detected anatomical changes. Both behavioral and anatomical findings are typical for schizophrenia mouse models.

Now we focus on early developmental changes in MIM expression and brain ventricle enlargement.

Jolanta Lundgren

Genetic mutations and alterations in the expression levels of myosin XVI are associated with neuropsychiatric disorders, including autism spectrum disorders (ASD) and schizophrenia. Excitatory and inhibitory synapses are differentially affected leading to an imbalance in synaptic output. Through its actin regulating properties, myosin XVI is involved in the control of dendritic spine morphology and function. Hence, elucidating the effects of increased vs decreased levels of myosin XVI on dendritic spine morphology and density, as well as on the excitatory/inhibitory synaptic balance, is of importance for understanding the role of myosin XVI at the synapse and in ASD and schizophrenia.

Goal of research: To understand how alterations in myosin XVI protein levels affects the excitatory/inhibitory synaptic balance and synaptic morphology and density.

Impact: Myosin XVI has not been extensively studied in general and its role in ASD and schizophrenia in particular is understudied. This project will elucidate the synaptic effects of altered levels of myosin XVI, which is particularly relevant for the understanding of the synaptic alterations in ASD and schizophrenia.

Methods: Primary hippocampal neurons will be manipulated to express decreased or increased levels of the myosin XVI protein. Excitatory and inhibitory synapses will be stained in order to enable detection of differences in their levels. Possible effects on the morphology and density of the synapses will also be analysed.

David Micinski

The axon initial segment, located at the junction between the soma and axon of neurons, is perfectly situated to carry out its two main tasks: maintaining neural polarity and serving as the site for action potential generation. Recent research suggests actin structures are involved in AIS plasticity, maintenance, and vesicle sorting. However, very little is known about how actin is regulated in the AIS and the proteins involved. Thus, we are focusing on elucidating how dynamic actin structures and actin-binding proteins in the AIS contribute to its function by utilizing genetic and pharmacological manipulations in cultured neurons. We make use of both diffraction-limited and super-resolution microscopy.

Pushpa Khanal

Different subclasses of the BAR-domain protein family are known to give rise to positive and negative membrane curvature. Previous studies in the lab have discovered an I-BAR domain-containing protein called MIM that initiates new dendritic spines by locally curving the membrane of the dendrites. However, since MIM knock-out does not fully abolish dendritic spine formation, there must be other proteins involved in dendritic spine initiation.

In this project, we have tested different subclasses of the BAR-domain protein family. Out of several candidate proteins we have tested, GAS7 was identified as the most promising candidate for dendritic spine initiation. Overexpression of GAS7 in rat hippocampal neuronal cultures increased the density of dendritic spines. Studies in rat hippocampal neuronal cultures as well as in organotypic hippocampal slices indicate that GAS7 is localized to dendritic spines as well as to patches on the dendritic shaft’s plasma membrane. Live cell time-lapse imaging showed that the localization of these patches correlate with new spine formation. Moreover, treatment of organotypic hippocampal slices with bicuculline (GABAA a receptor antagonist) leads to enrichment of the localization of GAS7 to the dendritic shaft patches. This evidence suggests that GAS7 is a novel dendritic spine initiation factor that can induce the formation of new spines in an activity-dependent manner.