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.

ARHGAP22 DISRUPTION AFFECTS RAC1 SIGNALING PATHWAY AND RESULTS IN ALTERED FORMATION AND FUNCTION OF GLUTAMATERGIC SYNAPSES IN MOUSE HIPPOCAMPUS / A. Longatti ; coordinatore: A.L. Catalano; tutor: F. Gardoni; co-tutor: M.Passafaro. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2018 Jan 25. 30. ciclo, Anno Accademico 2017. [10.13130/a-longatti_phd2018-01-25].

ARHGAP22 DISRUPTION AFFECTS RAC1 SIGNALING PATHWAY AND RESULTS IN ALTERED FORMATION AND FUNCTION OF GLUTAMATERGIC SYNAPSES IN MOUSE HIPPOCAMPUS

A. Longatti
2018

Abstract

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.
25-gen-2018
Settore BIO/10 - Biochimica
Settore BIO/13 - Biologia Applicata
Settore BIO/11 - Biologia Molecolare
RhoGTPases; Arhgap22; glutamatergic synapses; Rac1
GARDONI, FABRIZIO
CATAPANO, ALBERICO LUIGI
Doctoral Thesis
ARHGAP22 DISRUPTION AFFECTS RAC1 SIGNALING PATHWAY AND RESULTS IN ALTERED FORMATION AND FUNCTION OF GLUTAMATERGIC SYNAPSES IN MOUSE HIPPOCAMPUS / A. Longatti ; coordinatore: A.L. Catalano; tutor: F. Gardoni; co-tutor: M.Passafaro. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2018 Jan 25. 30. ciclo, Anno Accademico 2017. [10.13130/a-longatti_phd2018-01-25].
File in questo prodotto:
File Dimensione Formato  
phd_unimi_R10923.pdf

Open Access dal 23/07/2019

Descrizione: tesi dottorato completa
Tipologia: Tesi di dottorato completa
Dimensione 3.08 MB
Formato Adobe PDF
3.08 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/545287
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact