July 26, 2013. Nicotinic α7 acetylcholine receptors enhance the firing of prefrontal cortex “delay cells” that underlie working memory, according to a new study published July 16, 2013, in the Proceedings of the National Academy of Sciences. Led by Min Wang at Yale University in New Haven, Connecticut, the study also found that stimulation of these receptors was necessary for the action of N-methyl-D-aspartate (NMDA) glutamate receptors in the same brain region. The results suggest a mechanism for how genetic risk variants in α7-nAChRs may lead to working memory deficits in schizophrenia.
Dysfunctional nicotinic α7 receptors (α7-nAChRs) have been proposed to underlie the cognitive deficits of schizophrenia (see SRF related news story). The gene for the receptor CHRNA7 was associated with schizophrenia in several genetic studies, and knockout mice display cognitive impairments (Stephens et al., 2012). The α7-nAChR has also emerged as a viable drug target for schizophrenia (Olincy and Freedman, 2012). For example, in a preliminary study, the agonist tropisetron improved cognitive deficits in the illness (see SRF related news story).
Behavioral studies suggest that the neurotransmitter acetylcholine is important for working memory—the short-term maintenance of small amounts of information in order to guide future thought processes—which is impaired in schizophrenia (Croxson et al., 2011). The dorsolateral prefrontal cortex (DLPFC), a brain region whose dysfunction is also well documented in the illness, appears to be central to working memory. Although animal studies have demonstrated that α7-nAChRs agonists can improve working memory deficits induced by blocking NMDA receptors, the role of α7-nAChRs in DLPFC circuits is unknown.
Delay cell pharmacology
First author Yang Yang trained monkeys to perform a spatial working memory paradigm, the oculomotor delayed response (ODR) task. A cue is flashed at one of eight locations on a screen, and the monkey must use working memory to remember this location during a 2.5-second delay. At the end of the delay, the monkey moves its eyes to the correct location to receive a reward.
To examine the physiological actions of α7-nAChRs, the researchers made electrophysiological recordings from single neurons in the DLPFC while the monkeys performed the ODR task. They concentrated on “delay cells,” those neurons with persistent firing during the delay period that are responsible for generating mental representations of visual space—a central component of visual working memory. Each of these neurons has a so-called preferred direction, a portion of visual space for which it fires most strongly.
Application of the general nAChR antagonist mecamylamine reduced neuronal firing during all timepoints of the task. In contrast, the more specific α7-nAChR antagonist methyllycaconitine reduced the delay-related firing for the neuron’s preferred direction (with no effect on its non-preferred direction or firing during the presentation of the cue). These data suggest that α7-containing nAChRs can excite DLPFC neurons and point to a role for these receptors in spatial working memory. In addition, they provide an explanation for how risk variants in CHRNA7, which presumably disrupt α7-nAChRs, could lead to cognitive deficits in schizophrenia.
In contrast with the antagonist data, application of the α7-nAChR agonist PHA543613 enhanced delay-related firing, with an inverted-U dose effect observed. The most specific boost to firing during the delay period occurred with lower doses of the drug, while higher doses produced nonspecific increases in excitability. Similarly, low doses of the drug improved performance on the ODR task, while higher doses had no effect or were impairing. Therefore, selecting the appropriate dosage will be critical to the efficacy of α7-nAChR-based cognitive-enhancing drugs to treat schizophrenia and other disorders, say the authors.
Mingling of glutamate and acetylcholine
Given that NMDA receptors are also involved in the spatial tuning of delay-related firing, the authors next examined the interactions between these glutamate receptors and α7-nAChRs. Consistent with a previous report from the authors (Wang et al., 2013), blockade of NR2B NMDA receptors with the selective antagonist Ro256981 reduced delay-related firing. However, this reduction was reversed with co-application of PHA543613. Coupled with their electron microscopy findings that α7-nAChRs are prominent in the postsynaptic density of glutamatergic synapses, where NR2B-NMDARs are also located, the authors conclude that their findings are consistent with a “spatial and functional interaction of the two receptors.”
Given the proximity of the receptors at the postsynaptic density, the authors hypothesized that α7-nAChRs may provide the depolarization necessary for NMDA receptor neurotransmission. Consistent with their hypothesis, pharmacological blockade of α7-nAChRs abolished the NMDA application-associated increase in delay cell firing, demonstrating that stimulation of α7-nAChRs is required for NMDA action. The results suggest a mechanism by which acetylcholine shapes mental states, say the authors. They suggest that because the neurotransmitter modulates arousal—it is released during wakefulness but not sleep—α7-nAChRs may act to bring NMDA receptor higher cortical circuits online, thereby generating a “conscious cognitive state.”—Allison A. Curley.
Yang Y, Paspalas CD, Jin LE, Picciotto MR, Arnsten AF, Wang M. Nicotinic a7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. Proc Natl Acad Sci U S A . 2013 Jul 16 ; 110(29):12078-83. Abstract