NRSC 4032_ Extra Credit

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Jan 9, 2024

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AMPA Receptor Regulation of Trafficking and Endocytosis and its Role in Forgetting and Memory Decay Section 1 : Introduction and Background Recent advances in neuroscience have made great strides in the mechanisms behind memory formation and retention. Through the utilization of various methods of research including animal testing using both behavioral and in vitro methods, the acquisition and degradation of memories are becoming better understood. In these models, synaptic plasticity is becoming a crucial topic of study in the linkage to memory and learning (Lynch, 2004). Synaptic transmission strength is regulated by synaptic stimulation that is referred to as long-term potentiation (LTP) (Henley, Jeremy M., 2011). Although it has not yet been confirmed as to what degree or significance LTP has on memory, it has been discovered to be a biological substrate for some types of memory. A significant contributor to the expression of long-term potentiation is α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulation, an ionotropic receptor for the neurotransmitter glutamate. There is another significant glutamate receptor that functions along with AMPA receptors called N-methyl-D- aspartate (NMDA) receptors, but these will not be the focus of this research paper. AMPA receptor endocytic and exocytic trafficking into the postsynaptic density (PSD) is critical for synaptic potentiation and expression of LTP. This constitutive trafficking reveals consistent turnover of AMPAR containing GluR/2/3 subunits due to their interaction with several cytoskeletal proteins (such as N-ethylmaleimide-sensitive factor) (Lynch, 2004). Tocco et al. found that AMPA receptor binding in the PSD was increased in animal models following classical conditioning training (Tocco, 1991). In similar studies, inhibition of AMPA receptors led to retrograde amnesia in rats who experienced inhibitory avoidance training (Cammarota,

Bernabeu, Izquierdo, Medina, 1996). These consistent postsynaptic density modifications are highly influential in long-term potentiation and play an important role in forgetting and memory decay. The research question being reviewed is: what role does AMPA receptor trafficking and endocytosis have in forgetting and memory decay? By gaining insight into the mechanisms behind LTP with regard to AMPA receptor modulation, there can be an understanding of the specific influences that receptors have on memory retention and decay. This information is essential in the utilization of therapeutic and clinical methods to help reduce issues associated with memory loss, such as Alzheimer’s and dementia. These diseases currently have minimal available treatment, and furthering research on the mechanisms for forgetting could offer a novel treatment method. Clinical applications of this information will be the most beneficial and could offer new therapeutic care plans. There are a vast series of reversible conditions associated with memory loss including emotional disorders, head trauma, or brain diseases (Mayo Clinic, 2019). These reversible memory loss conditions could also benefit greatly from the advances to be made from AMPA receptor constitutive trafficking and regulation. By understanding the impact that AMPA receptors specifically have within synapse potentiation we will be able to target the receptors using pharmacological agents such as agonists or antagonists for this location. The study of AMPA receptors has the theoretical importance of giving a more in-depth insight into the process of memory formation, consolidation, and decay (Henley, Jeremy M., 2013). Because the study of memory is a series of theoretical concepts that indicate the influence that experience has on behavior. These topics are not able to be directly observed (Rudy, 2021). This specialized research can also provide better spatial modeling of the processes that occur during LTP and forgetting processes within the synapse and synaptic cleft. The practical application of furthering

research on AMPA receptors within the PSD is to incorporate this knowledge into the treatment of patients facing memory loss or decay. This also has the ability to help people grow to retain more information in the future more effectively. This topic relates to the course by talking about the role of glutamate receptors as seen in “Chapter 3: Generating Long-Term Potentiation”. It reviews the mechanism of AMPA receptor trafficking into dendritic spines as well as recycling endosomes (Rudy 2021). Section 2: Review of Related Research Reports The article being reviewed is “Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease” by Margaret O'Connor, Yang-Ping Shentu, Guan Wang, Wen-Ting Hu, Zhen-Dong Xu, Xiao-Chuan Wang, Rong Liu, and Heng-Ye Man. The aim of this study is to determine the impact that reduction of AMPA receptors has on Alzheimer's Disease. The researchers’ hypothesis is that the reduced AMPA receptor stability caused by AMPA receptor reduction leads to Alzheimer's Disease. They predict that by restoring the AMPA receptors within, the synapse will allow for an increase in cognitive function and synaptic strength in Alzheimer's Disease. They theorize that the reduction of AMPA receptors is the initial step leading to the cognitive deficits in Alzheimer's. The rationale behind this hypothesis is that the cognitive dysfunction seen in Alzheimer's disease is due to the decrease in AMPA receptor count and localization within the synapse, causing dysfunction in synaptic plasticity and weakened synaptic activity. There was evidence found that lysine acetylation on AMPA receptors causes an increase in protein accumulation and AMPA stability. The experimental design for the reduction of AMPA receptor acetylation due to Aβ Treatment utilizes hippocampal neurons with immunocytochemistry. Aβ oligomers were tested to have an

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impact on AMPA receptor expression. They then treated each group with Aβ and probed for synaptic GluA1. The independent variable is the addition of Aβ oligomer treatment. The dependent variable is the decrease in AMPA receptor acetylation. Results show that there was a significant decrease in acetylation within precipitated GluA1. Postmortem Alzheimer's Disease patients were examined for lysates to determine acetylation. Results conclude that each showed a significant decrease in GluA1 acetylation compared to controls. These results indicate that Aβ- induced reduction within the AMPA receptor stability and contributes to cognitive discrepancies in Alzheimer's Disease. There were many subsequent studies completed within this study, including one with mice as an animal model. The conclusion that this research has drawn is that the acetylation of AMPA receptors causes the obstruction of Aβ-induced reduction of AMPA receptors by stopping receptors’ internalization. This shows that there would be a benefit to increase AMPA receptor acetylation as a clinical treatment for patients with Alzheimer's Disease. The data does support the conclusions of the article with clear controls and error calculations. A major flaw that exists within the article is the assumption that the primary neurons used in the models were from a mouse model and could not translate the same results onto human medicine practice. There appear to be no other clear alternative hypotheses that fit the data as well as the authors’ interpretations (O'Connor, Margaret, et al., 2020). The article being reviewed is “Blocking Synaptic Removal of GluA2-Containing AMPA Receptors Prevents the Natural Forgetting of Long-Term Memories” by Paola Virginia Migues, Lidong Liu, Georgina E. B. Archbold, Einar Ö. Einarsson, Jacinda Wong, Kyra Bonasia, Seung Hyun Ko, Yu Tian Wang, and Oliver Hardt. The purpose of this study was to focus on the utilization of reducing GluA2-Containing AMPAR removal to prevent the loss of long-term memories. Although this article reviews several separate infestations on this topic, reviews on

the most relevant will be included. The researchers hypothesized that by blocking the removal of Glu-A2-containing AMPARs, the retention of long-term memory will increase within several models. They predicted that by infusing GluA23y into the dorsal hippocampus, they will be able to prevent the loss of long-term object location memories. This infusion will cause the reduction of synaptic internalization. A similar completed study shows the delay of GluA23y infusions to stop the decay of long-term object location memories, as well as interfering with AP2-dependent GluA2/AMPA receptors removal. This study predicted that the object location memories will be increased with long-term memories following the addition of the treatment. The rationale for this hypothesis given is GluA2-containing AMPA receptors play a crucial role in long-term memory retention. This led to the hypothesis and experimental design of using rats to test whether their synaptic removal determines memory loss. The experimental design for each experiment uses rats as the model. The set parameters given were that long-term objection location memories are forgotten following 10 days. Rats were tested for different object location memories after various days of training, and control rats were included. The independent variable within this experiment is the infusion of the GluA23y into the dorsal hippocampus at different periods of time. The dependent variable is memory retention, which is determined by seconds spent exploring. The results indicate that by infusing GluA23y into the dorsal hippocampus, there was a reduction in forgetting long-term object location memories. The conclusions made by the authors are that this highly regulated memory system, when deregulated, can cause memory decay and cognitive disorders. The data do support the conclusions, but there are a few large flaws in the experimental design. The major flaw is that animal models are assumed to represent human models in the way they behave and interact with the treatments. There appear to be no other hypothesis or explanations that fit the data (Migues, Paola Virgina, et al., 2016).

The article being reviewed is “MEF2A regulates mGluR-dependent AMPA receptor trafficking independently of Arc/Arg3.1” by Ruth E. Carmichael, Kevin A. Wilkinson, Tim J. Craig, Michael C. Ashby & Jeremy M. Henley. The purpose of this paper is to examine the transcription factor MEF2 as a negative regulator of learning or memory. This is thought to be completed by regulation of AMPA receptor trafficking of the GluA2 subunit. The researchers’ hypothesis is that using the knockdown of endogenous MEF2A, the highly specific mechanisms involving Group I metabotropic glutamate receptor internalization will be regulated. The outcome predicted is that MEF2A will allow for the decrease of internalization of Glu2A AMPA receptors without changing the expression of trafficking to these areas. The rationale for this hypothesis is that the Myocyte enhancer factor 2 (MEF2) is an important regulator in synapse differentiation, formation, and plasticity, and these are the regulators for synapse elimination in metabotropic glutamate receptors. It is theorized that AMPA receptor trafficking is controlled through MEF2 regulation of memory formation in vivo . The experimental method includes animal model rats as the subjects. The cortical neuronal cultures of the rats are infected to produce various outcomes with the target of the MEF2A transcript. The independent variable in this experiment was the treatment of shMEF2A to the hippocampal neurons. The dependent variable was the expression of Glu2A AMPA receptors. Results show that MEF2A expression will not change the AMPA receptor expression in basal conditions. They also show that the MEF2A knockdown stops GluR reduction in the AMPA receptor expression. The data conclusions indicate that there is a requirement for the MEF2A transcription factor in the internalization of mGluR-dependent AMPA receptors which alludes to its role in memory formation. The data do support the conclusions that are outlined in the article. One of the flaws that exist within the experimental design is the assumption that rat models will have the same

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response to treatment as human models. There do not appear to be any other reasons for the outcomes that the researchers did not consider (Carmichael, Ruth E, et al., 2018). Section 3 : Conclusion (2-4 pages). Overall, the research that focuses on AMPA receptors and their involvement in forgetting and memory decay is still in its infancy. Although there is no direct way to associate memory and learning directly to outcomes of experiments, the researchers show very similar goals in the outcomes of their data. The studies that were reviewed led to new information regarding AMPA receptors and the ability to utilize their specific mechanisms in order to combat memory decay. However, there is a very strong struggle within the neuroscience community to complete human trials which may be the step that need to be taken. The fact that each of the studies use animal models and each were rats shows that they have not led to be a better model for thinking about the question. Theoretically, these studies are looking to increase memory retention, so they should ideally have no harmful side effects. The fact that there are no human trials completed on the studies reviewed shows that there is a certain level of uncertainty involved that is not worth the risk from an ethical standpoint. The studies reviewed lead to new information surfacing about GluA2 AMPA receptors’ importance in memory retention and its ability to be directly targeted to yield results. These data provide insights that are ground-breaking and could lead to novel clinical treatments from diseases and traumas associated with memory loss. A notable theme was shown between a majority of the experiments that have been completed on AMPA receptors and their regulation. The study “Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease” and “Blocking Synaptic Removal of GluA2- Containing AMPA Receptors Prevents the Natural Forgetting of Long-Term Memories” had

very similar processes and methodologies. Each of these studies produced outcomes that supported each other’s hypotheses. In short, the Glu2A subunit of AMPA receptors can be selectively targeted for therapeutic drugs to decrease forgetting. To integrate and synthesize the results from the studies that have been reviewed, human models should begin to be used within the field of neuroscience. Even if this is a far reach from the current possibilities within the field, strides should be made in utilizing different animals as models. Another possible model that would be very far from current methods is to look at neuroscience research as a case-by-case experiment. By individualizing experiments to 1-3 subjects rather than numerous animal models, there could be a larger impact on the knowledge gained. For example, within the course, The Case of Henry Molaison was reviewed (Rudy, 2021). This case shows that one single human subject was able to provide a massive impact on the scientific community. It is possible that if these types of cases are sought out in a clinical setting, they could have to potential to provide a greater pool of subjects, and thus uncover more information that would otherwise be completely inaccessible. Future studies on this topic should examine the implication of utilizing these treatments to target the Glu2A subunit of AMPA receptors and view the intensity of the memory retention. The animal models used would limit this due to the restrictions of not having conscious recollection. For the article reviewed titled “MEF2A regulates mGluR-dependent AMPA receptor trafficking independently of Arc/Arg3.1”, I would recommend that future studies review how transcription factors play a role in these various processes including AMPA receptor trafficking, endocytosis, and degradation. A single transcription factor was reviewed in this article, and there is a selection of many various types of transcription factors that cause large impacts on memories and learning. The article brings up a future topic to review that would be

interesting to examine. It states that the MEF2A transcription factor should be studied for which genes mediate its effect. This would be very important to see how memory formation and retention varies in different individuals. Works Cited

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Cammarota M, Bernabeu R, Izquierdo I, and Medina JH. Reversible changes in hippocampal 3H-AMPA binding following inhibitory avoidance training in the rat. Neurobiol Learn Mem 66: 85–88, 1996. Carmichael, Ruth E, et al. “MEF2A Regulates MGluR-Dependent AMPA Receptor Trafficking Independently of Arc/Arg3.1.” Nature Scientific Reports , 27 Mar. 2018, www.nature.com/articles/s41598-018-23440-0 . Henley, Jeremy M. “AMPA Receptor Trafficking and the Mechanisms Underlying Synaptic Plasticity and Cognitive Aging.” National Center for Biotechnology Information , Mar. 2013, www.ncbi.nlm.nih.gov/pmc/articles/PMC3622464/ . Henley, Jeremy M. “Routes, Destinations and Delays: Recent Advances in AMPA Receptor Trafficking.” ScienceDirect , May 2011, https://doi.org/10.1016/j.tins.2011.02.004 . Lynch, M A. “Long-Term Potentiation and Memory.” PudMed.gov , Jan. 2004, https://pubmed.ncbi.nlm.nih.gov/14715912/ . Migues, Paola Virginia, et al. “Blocking Synaptic Removal of GluA2-Containing AMPA Receptors Prevents the Natural Forgetting of Long-Term Memories.” Journal of Neuroscience , 23 Mar. 2016, https://doi.org/10.1523/JNEUROSCI.3333-15.2016 . Mayo Clinic Staff. “When You Should Seek Help for Memory Loss.” Mayo Clinic , Mayo Foundation for Medical Education and Research, 19 Apr. 2019, www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/memory-loss/art- 20046326 . O'Connor, Margaret, et al. “Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease.” National Center for Biotechnology Information , 15 Aug. 2020, www.ncbi.nlm.nih.gov/pmc/articles/PMC7476873/ . Rudy, Jerry W. The Neurobiology of Learning and Memory . 2nd ed., Sinauer Associates, 2021. Tocco G, Devgan KK, Hauge SA, Weiss C, Baudry M, and Thompson RF. Classical conditioning selectively increases AMPA receptor binding in rabbit hippocampus. Brain Res 559: 331–336, 1991.

NRSC 4032_ Extra Credit

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