以N-甲基-D-天門冬胺酸受體功能低下小鼠模式評估肌胺酸對思覺失調症相關行為與認知缺損之療效

Abstract

Schizophrenia is a severe mental disorder, which results in tremendous cost to our society. The hypofunction of the N-methyl-d-aspartate (NMDA) glutamate transmitter system is an emerging hypothesis for schizophrenia, especially for negative and cognitive symptoms. This hypothesis has suggested promising pharmacological agents to ameliorate full range of schizophrenia symptoms. Based upon this hypothesis, therapeutic agents need to enhance the activity of NMDA receptor (NMDAR) via glycine modulation site for avoiding toxicity induced by overstimulation of glutamate binding sites. Glycine, a co-agonist at the NMDAR complex, is maintained at a low sub-saturating level in the vicinity of NMDAR by glycine transporter 1 (GlyT-1). To increase glycine level, sarcosine (N-methylglycine), a GlyT-1 inhibitor, can increase glycine concentration within synaptic cleft to facilitate NMDAR function. Despite emerging evidence on sarcosine in restoring NMDA hypofunction, the effective dosage and the mechanism for its therapeutic effect remain much unclear. In this thesis, three studies were designed and conducted to investigate the dosage and effect of sarcosine on the amelioration of behavioral and cognitive deficits in two mouse models of NMDAR hypofunction. In Study 1, we found that a single injection of sarcosine at low to medium doses (i.e., 250, 500 and 1000 mg/kg, i.p.) did not affect spontaneous locomotor activity in mice and no obvious toxicity was found in these mice as well. In Study 2, MK-801, a NMDAR antagonist, was used to induce schizophrenia-like behavior in male mice. A single administration of sarcosine (except the highest dose, 2000 mg/kg) had no effect on MK-801 induced hyperlocomotion and stereotypy. Intriguingly, a single injection of sarcosine at 1000 mg/kg can alleviate MK-801 induced cognitive deficits in the prepulse inhibition, holeboard task and fear conditioning task. In complementary to behavioral improvement, taking advantage of microPET scan with 18F-fluorodeoxyglucose to visualize brain activity, we also found that sarcosine can ameliorate the alteration of brain activity induced by MK-801 in male mice. In Study 3, serine racemase-null mutant (SR-/-) mice were further used as a genetic NMDAR hypofunction mouse model of schizophrenia. A single injection of sarcosine also successfully rescued observed behavioral and cognitive deficits reported in these male SR-/- mice. Collectively, our mouse models of NMDAR hypofunction that recapture some schizophrenia-like behavioral and cognitive deficits in mice can be ameliorated by a single injection of sarcosine. Findings from this research support the therapeutic effect of sarcosine and its potential in the treatment of schizophrenia.