ROLE OF RIN1 IN CONTROLLING FUNCTION AND PLASTICITY OF HIPPOCAMPAL SYNAPSES

Excitatory synapses undergo dynamic modifications in both structure and function to support synaptic plasticity, yet the molecular factors linking these processes are not fully defined. Prior work demonstrated that the Ras and Rab interactor protein 1 (RIN1) is abundantly expressed in excitatory neurons of the forebrain and may play a role in learning and memory processes and synaptic plasticity. At the molecular level, different domains of RIN1 have been shown to support the activation of Abl family kinases involved in actin cytoskeletal remodeling, and regulation of endocytosis via the small GTPase Rab5. Thus, RIN1 is well positioned to coordinate structural and functional changes during excitatory synaptic plasticity. We hypothesized that this dual function may allow it to orchestrate AMPA receptor trafficking and spine morphological changes.
To address this question, we first characterized synaptic properties and plasticity in hippocampal dissociated and organotypic cultures from RIN1 knockout versus wild-type mice. We find structural changes in spines that are not entirely mirrored by functional changes in basal synaptic transmission. However, converging evidence suggests that loss of RIN1 impairs both chemical and low frequency evoked LTD. These LTD deficits are rescued by postsynaptic reexpression of RIN1-WT, but not or only partially by RIN1 mutants with specific domain ablations. Our data suggest that RIN1 contributes to regulation of synaptic structure and activity dependent plasticity.