Effects of D-Serine on Visual Working Memory in Macaque Monkeys

Abstract

Schizophrenia is characterized by positive and negative symptoms along with cognitive symptoms that include impairment in working memory (WM). WM is the storage of relevant information for short intervals of time to guide thoughts and actions. The neural correlate of WM is thought to be the persistent activity exhibited during the retention interval of WM tasks. Persistent activity is hypothesized to be mediated by the activation of NMDA receptors (NMDAR) within recurrent neuronal circuits. Consistent with this hypothesis, studies with healthy humans and monkeys have shown that the administration of the NMDAR antagonist ketamine induces memory-load dependent deficits in WM, along with increasing response time. In parallel to this, the pathophysiology of schizophrenia has been hypothesized to rest on the hypofunction of NMDAR. Previous studies in humans indicate that blockade of NMDAR induces schizophrenia-like symptoms. In addition, symptoms of schizophrenia patients are alleviated with sub-chronic treatments focusing on the activation of the NMDAR co-agonist site. Based on these observations, I tested the hypothesis that increasing the activation of NMDAR with co-agonist stimulation has beneficial effects on WM. D-serine (100mg/kg/day-6 weeks) was orally administered to two female macaque monkeys performing a visual sequential comparison task (VCST), which allows the manipulation of memory load. In this task, the monkeys had to identify the location of a colour change within an array of 2 to 5 coloured stimuli following a retention interval of 1 second. I hypothesized that sub-chronic treatment with D-serine produces a gradual improvement in the monkeys’ performance on the VSCT. Specifically, I predicted that the improvement would scale with memory load due to increased demands on WM resources at higher loads. Contrary to my hypothesis, D-serine produced minute changes in response accuracy, which were not memory load-dependent. Also, the response latency of the monkeys was found to increase, which is commonly observed following NMDAR antagonist treatments. These findings suggest that D-serine has a limited role in increasing the activation of NMDARs to improve WM per se. The beneficial effects reported by NMDAR co-agonists in schizophrenic patients could be a general reduction in cognitive symptoms, not specifically related to WM.