Have you ever asked for a phone number only to forget it moments later? The only way to remember it is to rehearse the digits over and over in your head. This is an example of working memory, which is a type of short-term memory for storage and manipulation of information necessary for higher order cognition. Working memory is impaired in some diseases such as schizophrenia and Alzheimer’s. Since working memory is used for daily tasks, memory impairment often is associated with a reduced quality of life. If scientists can understand how the brain circuitry creates working memory, scientists may be able to treat the cognitive symptoms of diseases that impair working memory.
It has been known for quite some time that damage in a sub-region of the prefrontal cortex termed the dorsolateral prefrontal cortex (DLPFC) impairs working memory. However, until recently, the DLPFC circuitry has not been explored in great detail. One essential component to this circuitry is NMDA receptors, which are responsible for proper information signaling between neurons. NMDA receptors are activated by the neurotransmitter glutamate, which binds to the NMDA receptor, facilitating information signaling between the neurons. A disturbance in NMDA receptors in the DLPFC may contribute to such brain diseases as schizophrenia and Alzheimer’s (for review see Paoletti, Bellone, and Zhou, 2013). Postmortem studies of brains from humans with schizophrenia show structural abnormalities in the DLPFC related to NMDA receptors (Hashimoto et al., 2008). Similarly, Alzheimer’s neurons have a reduction in the amount of NMDA receptors (Snyder et al., 2005). These studies open the door to the investigation of NMDA receptor levels in patients with schizophrenia and Alzheimer’s disease. Unfortunately, conducting studies on humans is logistically challenging, so animal models are a good alternative to answering these complex questions.
A recent study using primates, an animal model similar to humans, demonstrated that NMDA receptors are involved with working memory (Wang et al., 2013). In this study, electrical recordings from the DLPFC of primates (monkeys) were obtained while they were engaged in a working memory task. This task (displayed in the figure to the left) consisted of presenting the monkey with a blank screen that only had a fixation cross, then displaying a circle on a screen in one of eight possible locations. The circle was then removed, and the monkey was required to hold the position of the circle in memory for 2.5 seconds. After this delay phase, the monkey indicated where the circle was previously located.
Under normal conditions, the monkey’s DLPFC neurons fired rapidly when holding the circle in their memory during the delay phase. Administration of a drug that blocks NMDA receptors reduced this firing rate in the DLPFC neurons during the delay phase. These results suggest that NMDA receptors in the DLPFC are important while engaged with a working memory task! These results may aid in the development of novel drug therapies that focus on changing the firing rate of neurons with NMDA receptors in the DLPFC, which may treat the working memory impairments found in people with schizophrenia and Alzheimer’s.
Written by Don A. Davies.
Hashimoto T., Arion D., Unger T., Maldonado-Avilés J.G., Morris H.M., Volk D.W., Mirnics K. & Lewis D.A. (2007). Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia, Molecular Psychiatry, 13 (2) 147-161. DOI: 10.1038/sj.mp.4002011
Paoletti P., Bellone C. & Zhou Q. (2013). NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease, Nature Reviews Neuroscience, 14 (6) 383-400. DOI:10.1038/nrn3504
Snyder E.M., Nong Y., Almeida C.G., Paul S., Moran T., Choi E.Y., Nairn A.C., Salter M.W., Lombroso P.J., Gouras G.K. & Greengard P. (2005). Regulation of NMDA receptor trafficking by amyloid-β,Nature Neuroscience, 8 (8) 1051-1058. DOI: 10.1038/nn1503
Wang M., Yang Y., Wang C.J., Gamo N., Jin L., Mazer J., Morrison J., Wang X.J. & Arnsten A.T. (2013). NMDA Receptors Subserve Persistent Neuronal Firing during Working Memory in Dorsolateral Prefrontal Cortex, Neuron, 77 (4) 736-749. DOI: 10.1016/j.neuron.2012.12.032