Abstract
BackgroundThe 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.ResultsHere, 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0206-6) contains supplementary material, which is available to authorized users.
Highlights
The majority of neurons within the central nervous system receive their excitatory inputs via small, actin-rich protrusions called dendritic spines
Given that RICH2 is a direct interaction partner of SH3 and multiple ankyrin repeat domains 3 (SHANK3) in the postsynaptic density (PSD) and that loss of SHANK3 has been linked to Autism Spectrum Disorders (ASD) in humans and animal models, we evaluated RICH2+/− and RICH2−/− mice for ASD – like behavior (Fig.5i, Additional file 4: Fig. S4a-g)
Taken together, we have seen that deletion of RAC1 GTPase activating proteins (GAPs) protein RICH2 leads to increases in spine volume and the number of spines with multiple head
Summary
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 altering the number and distribution of receptors and proteins at the post-synaptic membrane, thereby regulating synaptic input. Dendritic spines are the sites harboring the postsynaptic compartment of excitatory synapses These glutamatergic synapses in the central nervous system (CNS) are characterized by an electron dense structure underneath the postsynaptic membrane – the postsynaptic density (PSD). This highly dynamic protein network receives and integrates neurotransmitter signals. GTPases are activated by specific GEFs, the inactivation of the GTP-bound GTPases in turn is controlled by GAPs, which catalyze GTP hydrolysis [4, 5, 9, 10]
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