One approach to better understand the aetiology of ASD is to take candidate autism genes identified from human patients, generate mice conditionally mutant for these genes, and analyse functionally and structurally the neural circuits controlling these behaviours. A prevailing hypothesis for ASD occurrence is an early imbalance between excitation and inhibition in circuits associated with these behaviours, leading to an eventual underdevelopment of long-range connectivity paired with an overdevelopment of local circuits and disruption of cortical oscillations. The role of autophagy linked to de-regulated synaptic pruning in the aetiology of ASD is currently under intensive investigation.
We are working on an understanding of structural changes in neural connectivity in mice mutant for the high confident ASD gene cntnap2, a member of the neurexin family. Cntnap2 has been shown to function in the stabilization of synapses, while other members of the neurexin family have generally synaptogenic activities, that is the capacity to induce synapse formation.
We focus our analyses on parts of the medial prefrontal cortex, and the somatosensory cortex, that is regions believed to function as hubs to integrate neural circuits controlling social behaviours.
We are studying the development of circuits in these areas from early postnatal times to adult mice which enables us to detect (also) transient defects in neural circuit development.
To facilitate our analysis, we have generated cntnap2 mutant mice in which a small fraction of pyramidal neurons from layers 2/3 and 5 are specifically labelled, allowing high-resolution analyses of excitatory neural circuits, projection patterns, and synaptic connectivities.
We find transient disturbances in the density and form of dendritic spines of layer 2/3 and layer 5 pyramidal neurons which will affect the balance between excitation and inhibition in these areas. We are studying now a disruption of long-range projection patterns of these pyramidal neurons.
To understand the defects on a molecular level, we investigate the hypothesis that spine pruning is disrupted due to a disturbance of microglia function and/or neuronal autophagy in cntnap2 mutant mice. We investigate in parallel possible changes in the inhibitory circuitry of these mice.