Behavioural and synaptic pharmacotherapy of associative emotional memory in a model of mental retardation – RescueMemo

Mental retardation (MR) is defined as substantial limitation in intellectual function and adaptive behavior appearing during childhood. MR is defined by an overall intelligence quotient lower than 70 and associated with deficit in social and communication skills. The prevalence of MR is estimated around 3 %. In addition to be a human and familial burden, the societal cost of mental retardation is accompanied by an extremely high economical impact (estimated over 50 billion $, for MR patients born in 2000). The multiple heterogeneous origins of MR, from environmental to genetic, make it particularly challenging to understand. This proposal will focus on the ‘Fragile X? (FRAX) syndrome. The syndrome was named for the ‘Fragile site’ or unstained region of the X chromosome in affected individuals. FRAX is not only the most common inherited cause of MR, it also is the most common known cause of autism. Thus FRAX patients have significant social, emotional and cognitive problems along the FRAX spectrum, including autism spectrum disorder. Human imaging data suggest important alterations in brains structures controlling associative emotional memory. The underpinnings of the social cognition/emotional dimension of this disease are unknown. There are virtually no data concerning the impact of FRAX on brain structures implicated in associative emotional memory, as the vast majority of the physiological studies have, so far, focused on synaptic plasticity in the hippocampus. The cognitive/emotional dimension of FRAX, in spite of its central importance to the disease, remains largely unexplored. Our proposal aims at decyphering the abnormalities in synaptic functions responsible for the deficits in associative emotional memory and design new pharmacotherapy in a mice model of FRAX. To this aim we will: -Aim 1: Establish a synaptic and tri-dimensional portrait of synapses of two brain structures participating to associative emotional memory, the amygdala and the prefrontal cortex (PFC), in wild type and in a mice model of FRAX mental retardation (FMR1-/- mice). -Aim 2: Identify the synaptic and molecular underpinnings of normal and pathologic fear learning and extinction, by establishing an exhaustive portrait of amygdala and PFC neuronal circuits, following in-vivo emotional conditioning in wild type and FMR1-/- mice. -Aim 3: Based on the knowledge gained in Aims 1 & 2, we will design and test new pharmacotherapy in the hope to correct the abnormal emotional behaviors, synaptic malfunctions and molecular alterations that characterize FRAX mice. The following factors are major plus points to the success of this proposal: -The undisputed expertise of Dr. Gean laboratory (Partner 2, National Cheng Kung University, Tainan, Taiwan) in the study of the behavioral, molecular and physiological aspects of emotional memory. -The expertise of Dr. Manzoni (partner 1, INSERM U862, Bordeaux, France) in studying pathological adaptations of synaptic plasticity. -The already existing collaboration between the two laboratories (NSC/INSERM 2008-2009 travel fellowship) that allowed establishing strong human and scientific ties between the two groups. Funding this grant will allow getting novel insights on the molecular and synaptic substrates of the disease and testing new pharmacotherapy at the behavioral level in our mice models that can be rapidly translated to human subjects. While there is no current cure for the syndrome, there is hope that further understanding of its underlying causes would lead to design new therapies. In mental retardation in general and FRAX in particular, pharmacotherapy is possible.