Converging genetic, molecular and imaging data support the hypothesis that defects in the development of brain
networks may underlie the pathogenesis of psychiatric disorders such as autism spectrum disorders (ASD),
mental retardation, schizophrenia and affective disorders. In particular, recent genetic studies have succeeded to
identify single gene mutations or gene polymorphisms directly implicated in forms of these diseases and coding
for synaptic proteins (1, 2). Also, a frequent alteration often observed in animal models of genetic defects are
anomalies of dendritic spine morphology (3, 4), raising the possibility of defects in the formation and plasticity
of synaptic networks.  
The main objective of this WP is to take advantage of animal models of ASD, mental retardation, or affective
disorders to examine specific hypothesis about how building of synaptic networks could be disturbed. This will
be done by exploiting recent advances regarding the identification of specific genetic defects, the development of
new gene targeting methods in mice, but also technological developments that now allow to assess network
activity and connectivity through multiple electrophysiological recordings or imaging techniques.  
In the context of ASD, recent work has linked mutations in several candidate genes to autism and in particular
identified mutations in genes coding for neuroligins and neurexins, which encode a synaptic cell adhesion
complex implicated in the regulation of synapse formation (5). The mechanisms through which the behavioral
deficits are produced remain unknown, but recent evidence suggests a role of neuroligin/neurexins in the
regulation of the balance between excitatory and inhibitory transmission and connectivity. This possibility will
be examined through the generation of mouse models that recapitulate autism-associated genetic mutations and
focussing on the synaptic development of the cerebellum, olfactory and auditory cortices. Additionally,
experiments will be undertaken to directly assess the possibility of alterations of the formation of cortical
microcircuits.  As shown by both in vitro and in vivo studies, excitatory synapse assembly during development is
a very dynamic process that occurs through the continuous formation, elimination or replacement of dendritic
spines (6). These mechanisms are tightly controlled by sensory activity and properties of plasticity, so that small
perturbations of these mechanisms are likely to affect the construction and functional properties of cortical
microcircuits (7), leading to alterations of synaptic connectivity such as hyper- or hypoconnectivity or alterations
of the specificity of synaptic partners. This will be tested by assessing synapse dynamics, synaptic connectivity
or network function in specific genetic models of ADS and mental retardation.