51 Glutamate transporter polymorphisms Three independent groups have found that the 3′ region of SCL1A1 may contain a susceptibility allele for OCD, predominantly in male offspring.52-54 The protein product is

the high-affinity neuronal and epithelial transporter (EAAT3, EAAC1) for L-glutamate, L- and D-aspartate, and cysteine.55,56 EAAT3/EAAC1 is found in cortex, basal ganglia, and hippocampus, and has been detected in all parts of the neuron.57 In the adults, glutamate transport helps to keep extracellular glutamate below neurotoxic concentrations.58 EAAT3/EAAC1 exhibits rather low expression and makes a minor contribution to the removal of synaptic glutamate as compared with EAAT1 Inhibitors,research,lifescience,medical and EAAT2.59 During early brain development, it is expressed before astrocytes are functional. This is suggestive that EAAT3/EAAC1 is involved in the developmental role of glutamate.59 A critical role

of EAAT3/EAAC1 in neurodevelopment is consistent with the linkage and Inhibitors,research,lifescience,medical association findings supporting SLC1A1 as a primary candidate gene Inhibitors,research,lifescience,medical in not only pediatric OCD,52-54 but also in autistic spectrum disorders.60 Testosterone and prolactin regulate the expression of EAAT3/EAAC1 .56 The Selleck BX-795 increase in expression of EAAT3/EAAC1 by testosterone is consistent with the association of OCD with SLC1A1 being strongest in males.52,53 As for the possible function of the polymorphism, mice deficient in EAAC1 develop impaired self-grooming.55 This suggests that EAAT3/EAAC1 knockouts in pediatric OCD may be associated with increased rather than with decreased EAAT3 expression.

Glutamate receptor polymorphisms In addition to the glutamate transporter, Inhibitors,research,lifescience,medical the 5072T/G variant of NMDA subunit 2B gene (GRIN2B) has been associated with OCD in pediatric patients.61 Specifically, the 5072G-5988T haplotype was associated with OCD. GRIN2B, on chromosome 12p, encodes for the NR2B subunit of the ionotropic glutamate receptor. It is expressed mainly in the striatum and the prefrontal cortex.62 Inhibitors,research,lifescience,medical This consistent with regions demonstrating glutamatergic abnormalities in pediatric OCD patients.42,45 Furthermore, GRIN2B has been linked to schizophrenia,63 attention deficit hyperactivity disorder64 and bipolar disorder.65 During cortical development, GRIN2B is thought second to play a role in plasticity.66 In addition, neurotoxic levels of glutamate during the neonatal period increase the expression of NMDA NR2B in the striatum and cortex.67 Functionally, the increased expression of GRIN2B in reaction to excess glutamate68 suggests that pediatric OCD is associated with greater GRIN2B expression in the striatum. Most recently, a significant association was identified between the rs1019385 polymorphism of GRIN2B and decreased anterior cingulate cortex Glx but not with occipital Glx in pediatric OCD patients.