This study assessed social behavior in a mouse model of Fragile X syndrome (FXS), the Fmr1 (tm1Cgr) or Fmr1 "knockout" (KO) mouse. Both the KO and wild-type (WT) mice preferred to be near a novel conspecific than to be alone. However, during the initial interaction with a novel conspecific, (1) a greater proportion of the KO mice exhibited high levels of grooming; and (2) the average duration of nose contact with the stimulus mouse was significantly shorter for the KO mice, both indicative of increased arousal and/or anxiety. Both groups exhibited a robust novelty preference when the novel animal was a "preferred" mouse. However, when the novel mouse was a "nonpreferred" animal, both groups showed a diminished novelty preference but this effect was more pronounced for the WT mice. This blunted negative reaction of the KO mice to a nonpreferred animal may indicate that they were less proficient than controls in distinguishing between positive and negative social interactions. These findings provide support for the use of this animal model to study the autistic features of FXS and autism spectrum disorders.

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Multiple studies indicate that N-methyl-D-aspartate (NMDA) receptor hypofunction underlies some of the deficits associated with schizophrenia. One approach for improving NMDA receptor function is to enhance occupancy of the glycine modulatory site on the NMDA receptor by increasing the availability of the endogenous coagonists D-serine. Here, we characterized a novel D-amino acid oxidase (DAAO) inhibitor, compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and compared it with D-serine. Compound 8 is a moderately potent inhibitor of human (IC 50 , 145 nM) and rat (IC 50 , 114 nM) DAAO in vitro. In rats, compound 8 (200 mg/kg) decreased kidney DAAO activity by ϳ96% and brain DAAO activity by ϳ80%. This marked decrease in DAAO activity resulted in a significant (p Ͻ 0.001) elevation in both plasma (220% of control) and cerebrospinal fluid (CSF; 175% of control) D-serine concentration. However, compound 8 failed to significantly influence amphetamine-induced psychomotor activity, nucleus accumbens dopamine release, or an MK-801 (dizocilpine maleate)-induced deficit in novel object recognition in rats. In contrast, high doses of D-serine attenuated both amphetamine-induced psychomotor activity and dopamine release and also improved performance in novel object recognition. Behaviorally efficacious doses of D-serine (1280 mg/kg) increased CSF levels of D-serine 40-fold above that achieved by the maximal dose of compound 8. These findings demonstrate that pharmacological inhibition of DAAO significantly increases D-serine concentration in the periphery and central nervous system. However, acute inhibition of DAAO appears not to be sufficient to increase D-serine to concentrations required to produce antipsychotic and cognitive enhancing effects similar to those observed after administration of high doses of exogenous D-serine.

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