Enlarged dendritic spines and pronounced neophobia in mice lacking the PSD protein RICH2

Tasnuva Sarowar, Stefanie Grabrucker, Karl Föhr, Katharina Mangus, Matti Eckert, Juergen Bockmann, Tobias M. Boeckers, Andreas M. Grabrucker

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The majority of neurons within the central nervous system receive their excitatory inputs via small, actin-rich protrusions called dendritic spines. Spines can undergo rapid morphological alterations according to synaptic activity. This mechanism is implicated in learning and memory formation as it is ultimately altering the number and distribution of receptors and proteins at the post-synaptic membrane, thereby regulating synaptic input. The Rho-family GTPases play an important role in regulating this spine plasticity by the interaction with cytoskeletal components and several signaling pathways within the spine compartment. Rho-GAP interacting CIP4 homologue2/RICH2 is a Rho-GAP protein regulating small GTPases and was identified as an interaction partner of the scaffolding protein SHANK3 at post-synaptic densities. Results: Here, we characterize the loss of RICH2 in a novel mouse model. Our results show that RICH2 KO animals display a selective and highly significant fear of novel objects and increased stereotypic behavior as well as impairment of motor learning. We found an increase in multiple spine synapses in the hippocampus and cerebellum along with alterations in receptor composition and actin polymerization. Furthermore, we observed that the loss of RICH2 leads to a disinhibition of synaptic RAC1 in vivo. Conclusions: The results are in line with the reported role of RAC1 activity being essential for activity-dependent spine enlargement. Since SHANK3 mutations are known to be causative for neuropsychiatric diseases of the Autism Spectrum (ASD), a disintegrated SHANK3/RICH2 complex at synaptic sites might at least in part be responsible for abnormal spine formation and plasticity in ASDs.

Original languageEnglish
Article number206
Pages (from-to)28
JournalMolecular Brain
Volume9
Issue number1
DOIs
Publication statusPublished - 11 Mar 2016
Externally publishedYes

Keywords

  • Autism
  • Dendritic spine
  • Neophobia
  • Rac1
  • Shank3
  • Small GTPase
  • Spine morphogenesis, Phobia

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