Autism Spectrum Disorders (ASDs) comprise a heterogeneous group of neuro-developmental abnormalities with a strong genetic component, characterized by deficits in verbal and non-verbal communication, impaired social interactions, and stereotyped behaviors. In a small percentage of cases, ASDs are associated with alterations of genes involved in synaptic function. Although rare, these point to synapses as possible sites of ASDs origin. One class of non‑syndromic forms of ASDs has been found to be associated with mutations/deletions of genes encoding for neuroligins (NLGs). These are postsynaptic adhesion molecules that, interacting with their presynaptic partners neurexins, ensure the cross-talk between pre- and post-synaptic specializations and synaptic stabilization, necessary for maintaining a proper excitatory/inhibitory balance within local neuronal circuits. Here, transgenic mice carrying the R451C mutation of NLG3 (NLG3R451C KI) or lacking NLG3 (NLG3 KO mice), found in some families with autistic children, were used to study GABAergic signaling in the hippocampus at early stages of postnatal development. We hypothesized that activity‑dependent alterations in synaptic plasticity processes represent a convergent mechanism underlying neuro-developmental disorders including ASDs. Unlike littermate controls, NL3R451C KI and NLG3 KO pups failed to exhibit LTP following spike time dependent plasticity, a particular Hebbian type of learning, at immature hippocampal mossy fiber-CA3 synapses, known to express, at early developmental stages, a GABAergic phenotype. These results were associated with a dysfunction of BDNF/ TrkB signaling and could be rescued by exogenous application of BDNF. These data clearly show that an early dysfunction GABAergic signaling leads to alterations in the functional refinement of developing circuits and synaptic plasticity processes possibly underlying cognitive deficits in autistic children.
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