Improving cognitive training for schizophrenia using neuroplasticity enhancers: Lessons from decades of basic and clinical research.

Mounting evidence indicates that schizophrenia is a disorder that stems from maladaptive plasticity within neural circuits and produces broad cognitive deficits leading to loss of autonomy. A large number of studies have identified abnormalities spanning many neurotransmitter systems in schizophrenia, and as a result, a variety of drugs have been developed to attempt to treat these abnormalities and enhance cognition. Unfortunately, positive results have been limited so far. This may be in part because the scope of abnormalities in the schizophrenic brain requires a treatment capable of engaging many different neurotransmitter systems. One approach to achieving this kind of treatment has been to use neuroplasticity-based computerized cognitive training programs to stimulate the formation of more adaptive circuits. Although the number of studies implementing this approach has increased exponentially in recent years, effect sizes for cognitive gains have been modest and adherence to treatment remains an important challenge in many studies, as patients are often required to train for 40 h or more. In the present paper, we argue that cognitive training protocols will benefit from the addition of cognitive enhancers to produce more robust and longer lasting targeted neuroplasticity. Indeed, recent data from animal studies have provided support for combining plasticity-enhancing drugs with tailored behavioral training paradigms to restore normal function within dysfunctioning neural circuits. The advantages and challenges of applying this approach to patients with schizophrenia will be discussed.

D-serine prevents cognitive deficits induced by acute stress.

Increasing evidence indicates that acute stress disrupts cognitive functions mediated by glutamate-NMDA receptors, although the mechanisms are not fully understood. Here we investigated whether d-serine and glycine, the endogenous co-agonists of the NMDA receptor, are regulated by acute stress. We studied the biochemical and behavioral effects of acute restraint stress in C57BL/6 mice. Acute restraint stress decreased d-serine levels in the prefrontal cortex and glycine levels in the hippocampus. Behaviorally, acute stress impaired memory consolidation in the object recognition task and prepulse inhibition of the startle response. Importantly, d-serine administration (1 g/kg, i.p.) prevented both stress-induced impairments. Taken together, our results show for the first time an interplay between stress and d-serine and warrant further research on the role of d-serine in stress-related disorders.