Actin regulation in dendritic spines: From synaptic plasticity to animal behavior and human neurodevelopmental disorders
Year: 2019
Type: dissertation
Abstract: This thesis explores the role of several actin-binding proteins in the regulation of brain physiology with a focus on dendritic spines. Dendritic spines are considered the plausible physical substrate for learning and memory, as their morphology allows for modulating incoming signals. Disruptions in spine density and morphology are also often associated with neuropsychiatric disorders. The two cellular processes representing neuronal learning are long-term potentiation (LTP) and long-term depression (LTD). Here, I show that the actin-severing protein gelsolin transiently relocates to dendritic spines upon LTD induction, but not LTP induction or spontaneous neuronal activity. It is plausible that the modest – but relatively long-lasting – LTD-induced elevation of Ca2+ concentration increases the affinity of gelsolin to F-actin, thus inducing the relocalization of gelsolin to dendritic spines. Proper spine regulation is crucial for learning in live animals. 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 knock-out (KO) mice revealed defects in both learning and reverse-learning, alterations in anxiety levels and reduced dominant behavior, and confirmed the previously described deficiency in motor coordination and pre-pulse inhibition. Anatomically, we observed a decreased density of thin dendritic protrusions, enlarged brain ventricles and decreased cortical volume. Genetic studies have pointed out that genes often disturbed in neuropsychiatric disorders encode synaptic actin regulators. We selected five genes encoding different actin-regulating proteins and induced ASD-associated de novo missense mutations in these proteins. These mutations induced changes in the localization of α-actinin-4, which localized less to dendritic spines, and for SWAP-70 and SrGAP3, which localized more to dendritic spines. Among the wild-type proteins studied, only α-actinin-4 expression caused a significant change in dendritic spine morphology by increasing mushroom spine density and decreasing thin spine density. We hypothesized that mutations associated with ASD shift dendritic spine morphology from mushroom to thin spines. An M554V mutation in α-actinin-4 (ACTN4) resulted in the expected shift in dendritic spine morphology by increasing the density of thin spines. In addition, we observed a trend toward higher thin spine density with mutations in myosin IXb and SWAP-70. Myosin IIb and myosin IXb expression increased the proportion of inhibitory synapses in spines. The expression of mutated myosin IIb (Y265C), SrGAP3 (E469K), and SWAP-70 (L544F) induced variable changes in inhibitory synapses.
Source: Työväentutkimus Vuosikirja
Author: Iryna Hlushchenko
Institution: University of Helsinki
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2956396333