Impaired Sociability of the Balb/c Mouse, an Animal Model of Autism Spectrum Disorders, is Attenuated by NMDA Receptor Agonist Interventions: Clinical Implications

Impaired sociability is a domain of psychopathology that contributes significantly to the functional disability and poor quality of life of persons with Autism Spectrum Disorders (ASDs) (Brodkin, 2007; Crawley, 2004, 2007; Deutsch et al., 2011). Although cognitive functioning may influence the expression of impaired sociability, the relationship between cognitive deficits and impaired sociability is not a linear one; thus, for example, persons with ASDs whose IQs are in the near-normal to above normal range may manifest profound deficits of sociability that are similar to those shown by persons with ASDs and intellectual disability (Noterdaeme et al., 2010). Currently, there are no approved medications whose primary target is the domain of impaired sociability. The N-methyl-D-aspartic acid (NMDA) receptor is an example of a glutamate-gated ion channel that is comprised of four (or possibly five) constituent polypeptide subunits; it is located both preand postsynaptically (Millian, 2005). Each constituent polypeptide is an integral membrane protein that has external, transmembranous and internal domains. The constituent polypeptides align themselves within the lipid bilayer of the membrane to create a potential channel, whose opening depends on the membrane potential and the binding of L-glutamate and glycine. The duration and frequency of channel opening, which results in calcium ion conductance and membrane depolarization, are highly regulated. The properties of this ligand-gated ion channel receptor are influenced genetically by the combinatorial diversity of the constituent polypeptide subunits (i.e., expression and membrane insertion of specific subunits and their splice variants can affect channel properties); allosteric modulatory ligands (e.g., neurosteroids) (Deutsch et al., 1992); the extent to which the receptor is glycosylated and nitrosylated; and the extent to which the internal domain of receptor polypeptide subunits are phosphorylated (Marino & Conn, 2002). The phosphorylation state of the internal domain is influenced by cross-talk between specific signaling pathways and the NMDA receptor; for example, stimulation of metabotropic glutamate receptors co-localized with NMDA receptors on the cell surface can influence the extent of phosphorylation (Conn et al., 2009a; Marino & Conn, 2002). When the