Unraveling the impact of IL1RAPL1 mutations on synapse formation : towards potential therapies for intellectual disability

Abstract : Preserving the integrity of neuronal synapses is important for the development and maintenance of cognitive capacities. Mutations on a growing number of genes coding for synaptic proteins are associated with intellectual disability (ID), a neurodevelopmental disease characterized by deficits in adaptive and intellectual functions. The present work is dedicated to the study of one of those genes, IL1RAPL1, and the role of its encoding protein in synapse formation and function. IL1RAPL1 is a trans-membrane protein that is localized at excitatory synapses, where it interacts with the postsynaptic proteins PSD-95, RhoGAP2 and Mcf2l. Moreover, the extracellular domain of IL1RAPL1 interacts trans-synaptically with the presynaptic phosphatase PTPd. We studied the functional consequences of two novel mutations identified in ID patients affecting this IL1RAPL1 domain. Those mutations lead either to a decrease of the protein expression or of its interaction with PTPd, affecting in both cases the IL1RAPL1-mediated excitatory synapse formation. In the absence of IL1RAPL1, the number or function of excitatory synapses is perturbed, leading to an imbalance of excitatory and inhibitory synaptic transmissions in specific brain circuits. In particular, we showed that this imbalance in the lateral amygdala results in associative memory deficits in mice lacking Il1rapl1. Altogether, the results included in this work show that IL1RAPL1/PTPd interaction is essential for synapse formation and suggest that the cognitive deficits in ID patients with mutations on IL1RAPL1 result from the imbalance of the excitatory and inhibitory transmission. These observations open therapeutic perspectives aiming to reestablish this balance in the affected neuronal circuits.
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Mariana Ramos. Unraveling the impact of IL1RAPL1 mutations on synapse formation : towards potential therapies for intellectual disability. Neurons and Cognition [q-bio.NC]. Université Sorbonne Paris Cité, 2015. English. ⟨NNT : 2015USPCB058⟩. ⟨tel-01356238⟩

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