Synaptic pathophysiology in murin models of mental retardation – SynIQ

Mental retardation (MR) is a common condition characterized by significant limitation in intellectual function and adaptive behavior that arise during childhood. MR is defined by an overall intelligence quotient lower than 70 associated with deficit in social, daily living and communication skills, and is estimated to affect 1 to 3% of the population. Causes of MR are extraordinarily heterogeneous, ranging from environmental to chromosomal and monogenic causes. Conventionally, genetic forms of MR have been subdivided into syndromic and non-syndromic forms, depending on whether MR is associated or not with clinical, radiological, metabolic or biological features. To date nearly 300 MR-related genes have been identified and classified according to the associated syndrome. Many of those genes are involved in brain development, neurogenesis and/or neuronal migration. However, since some MR brains are normal in term of size and macro-architecture, it has recently been proposed that cognitive limitations may also arise from synaptic dysfunctions, a hypothesis supported by histological data. Indeed, post-mortem analysis of human MR brain tissue often shows dendritic spines with altered shapes and densities. The degree of these defects is correlated with the severity of MR and is consistently found in mouse models with genetically generated-MR, but also for non-genetic MR. Therefore alterations in the shape of dendritic spines are likely to be associated with or causal in cognitive deficits.
Functionally, much of what we know about synaptic deficits associated with MR comes from in vitro studies of MR mouse brains, i. e. obtained from animals bearing MR genes mutations mimicking the mutations found in humans. These mutations provide substantial evidence for the involvement of single gene in the pathogenesis of the disorder. Interestingly, over the last 20 years, over 90 X-linked MR genes have been identified from which several mouse models were generated.
From now, functional studies on MR-mouse models have been essentially performed onto the hippocampus and the cortex, two forebrain structures involved in learning and memory. However, due to the complexity of their neuronal microcircuits, correlations between cognitive and synaptic deficits remain difficult. In contrast, the role of MR-gene products in the physiology of other brain areas remains largely unknown, especially for mutations leading to non-syndromic MR, for which no or few functional data are available.
Based on our recent results showing that several MR mouse models exhibit functional synaptic deficits at cortical projections to the lateral amygdala, a structure involved in the coding of fear memory, we will examine the role of MR proteins in the process of memory formation at behavioral, cellular and molecular levels.
The first part of the project is designed to analyze morphological and physiological changes of cortico-LA synapses in mice submitted to fear conditioning. The synaptic analysis will be performed ex vivo using state of the art imaging and electrophysiological techniques on neurons involved in the memory trace. We will continue to examine the consequences of MR mutations onto local LA circuits and, with the help of collaborations, examine the generalization of the observed phenotypes to other brain structures exhibiting similar forms of synaptic plasticity. Ex vivo experiments will be completed by an in vitro approach on genetically manipulated cultured neurons. This will allow an ideal control of MR-gene expression and the use of imaging of living synaptic contacts at the nanometer scale and single molecule tracking of ionotropic glutamate receptors. This would deliver new information about the role of MR proteins in the control of excitatory synapses physiology and memory formation.