Glutamatergic synapses in neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) are a group of diseases whose symptoms arise during childhood or adolescence and that impact several higher cognitive functions such as learning, sociability and mood. Accruing evidence suggests that a shared pathogenic mechanism underlying these diseases is the dysfunction of glutamatergic synapses. We summarize present knowledge on autism spectrum disorders (ASD), intellectual disability (ID), Down syndrome (DS), Rett syndrome (RS) and attention-deficit hyperactivity disorder (ADHD), highlighting the involvement of glutamatergic synapses and receptors in these disorders. The most commonly shared defects involve α-amino-3-hydroxy-5-methyl- 4-isoxazole propionic acid receptors (AMPARs), N-methyl-d-aspartate receptors (NMDARs) and metabotropic glutamate receptors (mGluRs), whose functions are strongly linked to synaptic plasticity, affecting both cell-autonomous features as well as circuit formation. Moreover, the major scaffolding proteins and, thus, the general structure of the synapse are often deregulated in neurodevelopmental disorders, which is not surprising considering their crucial role in the regulation of glutamate receptor positioning and functioning. This convergence of defects supports the definition of neurodevelopmental disorders as a continuum of pathological manifestations, suggesting that glutamatergic synapses could be a therapeutic target to ameliorate patient symptomatology. Core mechanisms involved in the pathogenesis of NDDs. ASD (Autism Spectrum Disorder): Neurexin and neuroligins are transmembrane proteins localised in the pre- and post-synaptic compartments, respectively that interact each other in the synaptic cleft. Mutations in the gene encoding Neurexin-1, Neuroligin-3 and 4 have been found in patients affected by ASD. Neurexins regulate presynaptic vesicles release whereas neuroligins, through the interaction with PSD-95, affect NMDARs functioning. SHANK3 protein belongs to a class of scaffolding molecules and it is implicated in autistic phenotype in patients affected by Phelan McDermid syndrome. This protein regulates different glutamate receptors (NMDARs, AMPARs and mGluR5) through direct or indirect interactions mediated by PSD-95, SAPAP and Homer. Moreover, IGF-1 pathway has been found associated to Shank3-depletion defects. Mutations on the NMDARs subunit encoding genes GRIN2A and GRIN2B, are also directly affected by mutations in ASDs patients. ID (Intellectual Disability): FMRP prot