LINKING NMDA RECEPTOR-DEPENDENT PLASTICITY AND NEURONAL ARCHITECTURE: THE ROLE OF RING FINGER PROTEIN 10

An active synapse-to-nucleus communication is essential for long-term changes in neurons, like the regulation of neuronal plasticity and shaping neuronal morphology. Next to the fast electrochemical signaling, neurons employ a slower mechanism that involves a recently discovered class of proteins, the synaptonuclear messengers. Different studies showed the pivotal role of synaptonuclear messengers in the modulation of synaptic transmission at excitatory synapses. On the other hand, alterations of synaptonuclear messengers\u2019 activity have been correlated to synaptic failure as observed in different synaptopathies, including both neurodevelopmental disorders and neurodegenerative diseases. Ring Finger Protein 10 (RNF10) has been recently identified as a novel synapse-to-nucleus signaling protein that specifically links the activation of synaptic GluN2A-containing NMDA receptors (NMDARs) to gene expression. RNF10 synaptonuclear trafficking is responsible for the remodeling of dendritic spines that substance the postsynaptic modifications required for long-term potentiation (LTP). However, the molecular mechanisms leading to NMDAR/RNF10 complex disruption and for initiating the importin-mediated trafficking of RNF10 to the nucleus remain unclear. In this PhD project we investigated the molecular mechanisms that underlie RNF10 activation and in this matter we discovered a protein kinase C (PKC)-dependent phosphorylation event on RNF10-Ser31, which drives RNF10 synaptonuclear trafficking. Moreover, we show that pSer31-RNF10 plays a role both in synaptonuclear signaling and in neuronal morphology. In particular, the prevention of Ser31 RNF10 phosphorylation induces a decrease in spine density, neuronal branching, and CREB signaling, while opposite effects are obtained by mimicking a stable RNF10 phosphorylation at Ser31.Based on these results, we investigated the role of RNF10 in vivo, in the RNF10-/- mouse model. In particular we studied the putative involvement of the synaptonuclear protein in neurodevelopment, focusing our attention on the first three weeks of postnatal life, which represents the critical period for neuronal differentiation and synaptogenesis in rodents. We found that RNF10-/- mice have an alteration in brain morphology, in particular in the hippocampal area, and impaired cognition. At a microscopic level, RNF10-/- deficiency alters the molecular composition and the morphology of the glutamatergic synapse. In the CA1 region of the Hippocampus, dendritic arborization of RNF10-/- neurons is severely reduced and LTP induction is compromised. Overall, these results add novel information about the functional and structural role of synaptonuclear protein messengers in shaping dendritic architecture and regulating synaptic plasticity in hippocampal neurons. \u200