A. Longatti
ARHGAP22 DISRUPTION AFFECTS RAC1 SIGNALING PATHWAY AND RESULTS IN ALTERED FORMATION AND FUNCTION OF GLUTAMATERGIC SYNAPSES IN MOUSE HIPPOCAMPUS [Tesi di dottorato]
Università degli Studi di Milano, 2018-01-25

The regulation of actin cytoskeleton operated by RhoGTPases is crucial for neuronal morphogenesis, especially for neurite elongation and branching, synaptogenesis and synaptic plasticity. Dysregulation of RhoGTPases leads to neuronal dysfunctions including intellectual disability, schizofrenia and Alzheimer disease. Rac1 is a member of the RhoGTPase family and it has been demonstrated to positively regulate dendritogenesis and dendritic spines formation and maturation. As well as other RhoGTPases, Rac1 activity is regulated principally by two kinds of molecules: GEFs (guanine nucleotide exchange factors) and GAPs (GTPase activating proteins). Arhgap22 protein is a specific Rac1-Gap that promotes the inactivation of Rac1. Although it was previously reported that Arhgap22 transcripts is present in murine brain, its functions in neurons have not been studied yet. Here, we reported that Arhgap22 is expressed in mouse brain in a precise spatio-temporal window. Moreover, taking advantage of an animal mouse model knock out (KO) for Arhgap22, we described the effects of its silencing in hippocampal neurons. In vivo, Arhgap22 disruption led to an increase level of activated Rac1 and its downstream pathways, with a subsequent increase in dendritic spine density in CA1 region of hippocampus. Additionally, Arhgap22 lacking mice presented reduced AMPA receptors in the post-synaptic density of excitatory synapses and this alteration was reflected by the impairment in the induction and mainteinance of long-term potentiation (LTP). Arhgap22 KO mice presented also defects in cognitive tasks and decreased anxiety-like behaviours. In a nutshell, the results of this work suggested that Arhgap22 is a key regulator of Rac1 signaling and that affects the maturation of excitatory synapses, synaptic plasticity and cognitive functions.

diritti: info:eu-repo/semantics/openAccess
In relazione con info:eu-repo/semantics/altIdentifier/hdl/2434/545287
GARDONI, FABRIZIO
coordinatore: A.L. Catalano; tutor: F. Gardoni; co-tutor: M.Passafaro
CATAPANO, ALBERICO LUIGI
Settore BIO/10 - - Biochimica
Settore BIO/13 - - Biologia Applicata
Settore BIO/11 - - Biologia Molecolare


Tesi di dottorato. | Lingua: Inglese. | Paese: | BID: TD18003006