In Aging Cell, researchers have identified a receptor in the brain that appears to be responsible for cognitive problems after surgery, particularly in older people.
Surgery can cause cognitive problems
Neurological symptoms such as postoperative cognitive dysfunction [1] and postoperative delirium [2] are common after surgery, particularly when the surgery is intensive or the patient is older. These symptoms, known collectively as postoperative neurocognitive disorders (pNCDs), have been associated with inflammation but are largely poorly understood.
This research is focused on Nogo-66 receptor 1 (NgR1), a receptor that naturally restricts neuroplasticity [3], the ability of neurons to change shape and form new memories. Previous research has implied that it is a core reason why childhood trauma is difficult to forget for adults [4]. Other work has found that this protein instigates the spread of the disease in Alzheimer’s model mice [5] and that it interacts with amyloid beta [6].
The brains of healthy organisms can learn when and how to become more plastic [7]. This metaplasticity is regulated in part by receptors known as AMPARs, which are composed of four separate subunits [8]. Actin, specifically the ratio of F-actin to G-actin, affects how neurons grow and develop, regulates the function of AMPARs, and is key to neuroplasticity [9]. These researchers, therefore, hypothesized that NgR1 has effects in this area.
An increase in anxiety
In the first experiment, aged mice (20-22 months) were anaesthetized and had their abdominal regions opened (laparotomy). Compared to the control group, these mice had consistently greater levels of NgR1 in the hippocampus for a week, but this did not hold true for other brain regions. Its co-receptors, which are necessary for its function, were also similarly upregulated.
This was accompanied by several behavioral changes. Mice that had been subjected to surgery had increases in marble burying and grooming behaviors, and when given a choice between closed and open areas, spend less time in open areas than mice not subjected to surgery. This represents increased anxiety and fear memory. However, when a peptide known to be antagonistic to NgR1 (NEP1-40) was also administered to block its function, these behavioral changes were diminished to be indistinguishable from a control group given no surgery at all.
Potential protection on multiple levels
This behavioral protection was accompanied by protection for the synapses as well. In mice given surgery, PSD95, a marker of synaptic activity, was significantly reduced. However, mice given NEP1-40 with the surgery did not have this marker reduced. As expected, NEP1-40 reduced both NgR1 and the related compound NogoA.
The researchers found that this chemical protection has physical effects. Many aspects of CA1 pyramidal neurons in the hippocampus, including total length, intersections, and branching, were affected neither by surgery nor by NEP1-40. However, these neurons’ dendrites were significantly affected; the number of thin and stubby dendritic spines was unchanged, but the surgical group had fewer mature and healthy spines than the control group. NEP1-40 also reversed this change.
This was found to be directly related to changes to the F-actin/G-actin ratio, a benefit that was recapitulated in a cellular experiment. Multiple enzymes and proteins related to actin, both downstream and upstream, were affected by surgery and restored by NEP1-40. Likewise, AMPAR activity, specifically in the expressions of Glu1 and Glu2, was reduced by surgery and restored by NEP1-40. Calcium responses were found to be similarly affected.
Neuroplasticity is a long-known problem in the world of aging, not just in the context of surgery and trauma but in the learning ability of older people more generally. If NgR1 can be affected by interventions, it may be possible to restore some degree of learning and memory retention to older people, particularly those recovering from serious injuries. Much more work will need to be done, including drug discovery, to determine if this is the case.
Literature
[1] Alam, A., Hana, Z., Jin, Z., Suen, K. C., & Ma, D. (2018). Surgery, neuroinflammation and cognitive impairment. EBioMedicine, 37, 547-556.
[2] Jin, Z., Hu, J., & Ma, D. (2020). Postoperative delirium: perioperative assessment, risk reduction, and management. British journal of anaesthesia, 125(4), 492-504.
[3] Akbik, F. V., Bhagat, S. M., Patel, P. R., Cafferty, W. B., & Strittmatter, S. M. (2013). Anatomical plasticity of adult brain is titrated by Nogo Receptor 1. Neuron, 77(5), 859-866.
[4] Bhagat, S. M., Butler, S. S., Taylor, J. R., McEwen, B. S., & Strittmatter, S. M. (2016). Erasure of fear memories is prevented by Nogo Receptor 1 in adulthood. Molecular psychiatry, 21(9), 1281-1289.
[5] Wang, J., Qin, X., Sun, H., He, M., Lv, Q., Gao, C., … & Liao, H. (2021). Nogo receptor impairs the clearance of fibril amyloid‐β by microglia and accelerates Alzheimer’s‐like disease progression. Aging Cell, 20(12), e13515.
[6] Zhao, Y., Sivaji, S., Chiang, M. C., Ali, H., Zukowski, M., Ali, S., … & Wills, Z. P. (2017). Amyloid beta peptides block new synapse assembly by nogo receptor-mediated inhibition of T-type calcium channels. Neuron, 96(2), 355-372.
[7] Toyoizumi, T., Kaneko, M., Stryker, M. P., & Miller, K. D. (2014). Modeling the dynamic interaction of Hebbian and homeostatic plasticity. Neuron, 84(2), 497-510.
[8] Diering, G. H., & Huganir, R. L. (2018). The AMPA receptor code of synaptic plasticity. Neuron, 100(2), 314-329.
[9] Gu, J., Lee, C. W., Fan, Y., Komlos, D., Tang, X., Sun, C., … & Zheng, J. Q. (2010). ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity. Nature neuroscience, 13(10), 1208-1215.
