Cycle 5 project 3

Long-range neuronal connectivity in neurodevelopmental disorders


P03-AimePhD student: Aime Mattia, Italy
Home Institute: Bordeaux Neuroscampus; Principle Investigator: Yann Humeau
Host Institute: Amsterdam Neuroscience; Principle Investigator: Rhiannon Meredith

Executive Summary

Development of our cognitive abilities requires the correct formation of neuronal connections in brain circuitry. Abnormal brain activity and increased cortical neuron density occur in many intellectual disability (ID) disorders and autism1.Clinicians theorise that misregulated neuronal connectivity in the brain underlies cognitive impairments in neurodevelopmental disorders (NDDs)².

This NDD theory predicts that neurons are hyper-connected in local networks but hypo-connected in long-range pathways (Figure 1). We recently showed prominent hyper-connectivity in local medial prefrontal cortical networks of a genetic mouse model for intellectual disability and autism (Testa-silva et al., 2012)3. However, it is not known whether the predicted long-range connectivity impairment occurs at the level of synaptic neuronal circuitry within the brain in NDDs. The main aim of this ENC proposal is to validate the clinical theory that impaired long-range neuronal connectivity occurs in NDDs of autism and intellectual disability and to test the potential for correction with compounds currently in clinical trials.

In the last two years, many high impact articles revealed a vast range ofgenes and copy-number-variations associated with autism 4,5. However,no one single gene will explain the cognitive and behavioural impairments common to the range of autistic and intellectual NDDs. Validation of the NDD theory at a brain circuit level in syndromicgenetic mouse models has the potential to demonstrate a functional mechanism that can underlie and unify these deficits across different syndromes.
Our key approach is to investigate whether a prominent clinical theory from autistic patients is valid at the neuronal level in genetic mouse models for NDDs. Furthermore, we will test compounds currently in Phase IIbadult clinical trials6 in a novel manner, during early stages of brain development in genetic mouse models.

Our labs have strong complementary track records in cortical and amygdala synaptic physiology, in-house experience necessary for NDD mouse models and previous demonstration of pharmacological rescue strategies at behavioral and synaptic function levels in these mice. These techniques provide a solid working platform for the start of this ENC proposal and enable the project to be rapidlyestablished. In-house breeding colonies for NDD and ID mouse models are already available in Bordeaux and Amsterdam.We believe that this multidisciplinary approach to measure brain connectivity in different genetic mouse modelsis essential to demonstrate the direct link between long-range neuronal connectivity and autism disorders.

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