Cycle 1 project 2

Alterations in the neuronal connetivity of neocortical circuits are a crucial feature of cognitive defects in Fragile X Syndrome

 

PhD student: Matthias Georg Haberl, Germany
Home Institute: Bordeaux Neurocampus; Principle Investigator: Andreas Frick
Host Institute: Neuroscience Center Zürich; Principle Investigator: Kevan Martin

Executive Summary
Defects in cortical circuits have devastating neurological and psychiatric consequences.Fragile X Syndrome (FXS), the most common form of inherited mental retardation (MR) syndrome and most well characterized cause of Autism Spectrum Disorders (ASD), is caused by a silencing mutation of the gene Fmr1 (encoding the protein FMRP). In humans, the consequences of this disorder include hypersensitivity to sensory stimuli, autistic behavior, seizures, and learning and memory deficits. One of the morphological hallmarks of FXS is the presence of abnormalities in the shape/number of spines, the major sites for synaptic input. In addition, FMRP regulates the RNAs of molecules that determine the anatomical connectivity (cytoskeleton, axon and dendrite branching, spines) within cortical circuits. We therefore hypothesize that defects in the connectivity and information processing of neocortical circuits are a crucial feature of FXS. To address this hypothesis, we will probe changes in neuronal connectivity, and its consequence for information processing in the neocortical circuits of the barrel cortex (BC) in Fmr1 knockout mice. For this, we will use a combination of cutting-edge viral, imaging, and anatomical quantification approaches. We expect that our work will reveal new mechanisms involved in the pathology of FXS (and MR and ASD), and promises new knowledge about fundamental principles of normal circuit organization in general.

Hypothesis: Defects in the connectivity of neocortical circuits underlie sensory hypersensitivity in Fragile X Syndrome. This hypothesis is derived from recent findings that adult Fmr1KO2 mice exhibit hypersensitivity to whisker stimulation. These findings were based on gap-crossing behavioural experiments (Ginger, Celikel, Frick, unpublished), and preliminary voltage-sensitive dye measurements of population activity in layers (L) 2/3 of the barrel cortex (Ferezou, Ginger, Frick, unpublished). Together with several other studies this suggests defects in the connectivity of neocortical circuits resulting in changes in information processing.

To address this hypothesis we propose the following specific aims:

1. Investigation of connectivity defects in neocortical circuits of Fmr1KO2 mice. We will investigate the connectivity phenotype of sensory hypersensitivity in the neocortical L2/3 circuits of Fmr1KO2 mice. Particular attention will be given to the idea that sensory hypersensitivity might be caused by defects in the GABAergic circuits (d’Hulst & Kooy 2007; Selby et al., 2007; Gibson et al., 2008). To address this, we will use a combination of 2 monosynaptic trans-synaptic tracing, in vivo two-photon targeted single cell electroporation, and anatomical quantification methods.

2. Analysis of activity pattern defects in neocortical circuits of Fmr1KO2 mice. Using in vivo two-photon calcium imaging we will measure network activity in the barrel cortex of living animals during sensory stimulation and examine defects in the excitability and activity pattern of circuits Fmr1KO2 compared to wild-type mice. Mouse model and experimental system: The Fmr1 knockout (Fmr1KO2) mouse (Mientjes et al., 2006) is a model for FXS. The experiments will be performed in the whisker-related barrel cortex (BC). Adult Fmr1KO2 and wild-type (wt) mice 6-8 weeks of age will be used.

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