Ryanodine Receptor 2 (RyR2) underlies maintenance and remodeling of dendritic spines

Abstract

The human brain comprises 1012 neurons that receive, integrate and transmit electrochemical signals. This complex network constantly re-adapts during an animal’s lifetime. All sensed experiences refine neurons via activity-evoked processes that critically affect cognition and behavior. The most dynamic neuronal structure is the synapse, a microdomain that controls the transmission of electrochemical signals from cell to cell. Upon neuronal activation, post-synaptic dendritic spines change in number, morphology and strength. In adult excitatory neurons, structural and functional maturation of local spines mostly rely on Ca2+ influx from the extracellular space through glutamate ionotropic receptors. The subsequent release of Ca2+ from the endoplasmic reticulum (ER) occurs through Ryanodine Receptors (RyRs) and Inositol (1,4,5)-triphosphate Receptors (IP3Rs) via a mechanism known as Ca2+-induced calcium release (CICR). Despite the overwhelming research conducted over the past decades, the degree of involvement of CICR in synaptic plasticity is not completely understood. <br /> We previously highlighted that the endoplasmic reticulum Ca2+ channel ryanodine receptor 2 (RyR2) undergoes activity-dependent genetic re-programming, which alters the abundance of the channel in particular regions of the brain. The submitted thesis describes the contribution of RyR2, and its up-regulation, in dendritic spine homeostasis using different knockout models. Ryr2 deletion in adult neurons results in cell shrinkage and disturbs spine maintenance. Strikingly, the absence of RyR2 impairs spine biogenesis and remodeling in different paradigms of neuronal plasticity, as in the case of spatial training and administration of psychoactive drugs. Overall, these findings elucidate an underestimated mechanism of intrinsic plasticity, which controls neuronal morphology and has an impact on hippocampal memory acquisition.