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Title: The role of MSK1 in homeostatic plasticity from in vitro to in vivo
Author: Wauters, Sandrine
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2013
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Synaptic plasticity is the ability of neuronal synapses to strength and weaken from a set threshold determined by previous 'experience' thus representing a cellular basis for learning and memory. There are different forms of synaptic plasticity including Hebbian, homeostatic synaptic scaling as well as experience-dependent plasticity such as when animals are exposed to environmental enrichment (EE). Small protrusions which receive excitatory inputs known as dendritic spines are able to change morphology which has also been linked to trafficking of glutamate AMPA receptors (AMPAR) in response to neuronal activity. Brain-derived neurotrophic factor (BDNF) is a neutrophin involved in regulating both transcription and translation during synaptic plasticity. A plasticity-related gene, activity-regulated cytoskeleton-associated protein (Arc) controls the endocytosis of AMPAR nonetheless downstream signalling pathways are still largely unknown. The nuclear kinase, mitogen-and stress-activated protein kinase 1 (MSKI) regulates gene transcription in a BDNF-dependent manner. Thus we wanted to investigate whether MSKI plays a role in regulating Arc expression in response to BDNF-induced synaptic plasticity. In order to test this hypothesis we used MSKI kinase dead (MSK1 KD) transgenic mouse which had an inactivating knock-in mutation in the MSK1 N-terminus kinase domain. Dissociated hippocampal neurones were cultured from MSK1 KD and wild-type (WT) mice and stimulated with BDNF to monitor Arc protein expression. MSKI KD neurones showed a delayed response in BDNF-induced Arc upregulation. Interestingly in the presence of tetrodotoxin (TTX) which reduces BDNF levels, MSKI KD mice failed to show homeostatic scaling of synaptic transmission, Arc expression and spine morphological changes in vitro. After measuring the same parameters, EE-induced plasticity was unaffected in MSK1 KD adult mice but this may be a reflection of the experimental protocol used highlighted in the literature. The link between Arc and the cytoskeleton is unfamiliar and thus our finding of a novel interacting partner associated with clathrin-mediated endocytosis will carve out innovative mechanisms involved in synaptic plasticity. MSK1 acts an important homeostat during TTX-induced up-scaling of Arc protein and may influence structural effects on spine morphology. However MSKI may more of a local homeostat rather than generalised as its role in BDNF or experience-dependent stimulation was not as clear. Arc is an important synaptic mediator and thus linking it to the cytoskeleton could bridge the gap in understanding the mechanisms underlying learning and memory.
Supervisor: Not available Sponsor: Biotechnology and Biological Sciences Research Council ; GlaxoSmithKline ; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology