Mutazioni delle subunità dei recettori N-methyl-D-aspartate e ruolo nella patogenesi di malattie neurologiche e neuropsichiatriche

N-methyl-D-aspartate receptors, also known as NMDARs, are a family of ligand-gated ionotropic glutamatergic channels whose activity is regulated in response to the binding of their mandatory agonist glutamate and their co-agonist glycine (or eventually D-serine). Since the opening of NMDARs mediates an increase of intracellular Ca2+ levels only when the membrane is sufficiently depolarized, thanks to their coincidence detection, these receptors are considered as key players of many critical functions in the brain, among which synaptic plasticity, motor, sensory and cognitive functions, brain development and maturation. NMDARs are hetero-tetramers receptors, meaning that they are composed by 4 subunits which differs among themselves and which may be present in variable composition patterns. A big number of different mutations affecting the GRIN genes for NMDAR subunits have been found as the leading cause of a variety of neurological and neuropsychiatric diseases. The aim of this thesis is to try to better delineate the relationship occurring between the pathophysiology and symptomatology of several neurological disorders (such as schizophrenia, epilepsy, intellectual disability, autism spectrum disorders and attention deficit hyperactivity disorder) and the mutations found in NMDAR subunits. In particular, it will be evaluated the consequence of specific mutations affecting in particular three of the NMDAR subunits, GluN1, GluN2A and GluN2B, which are the most frequently associated with pathological conditions.