Key Points:
- For their CURE Epilepsy Multi-disciplinary grant, Dr. Audrey Yee, an epilepsy researcher and clinical neurologist based at the University of Colorado (now at the National Institute of Allergy and Infectious Disease), and Dr. Amy Yee, a breast cancer and Wnt signaling pathway researcher at Tufts University, used their different expertise to investigate novel mechanisms underlying epileptogenesis.
- Utilizing learnings from studies in cancer, the team was able to show that two different biological pathways, the Wnt pathway and the mTOR signaling pathway, are altered during epileptogenesis. Changes in these pathways contribute to an increased susceptibility to seizures. This study is the first to demonstrate the potential relevance of the Wnt signaling pathway in epileptogenesis and epilepsy.
- By revealing biological changes that happen during epileptogenesis, this work provides tangible therapeutic strategies that can be used to block epileptogenesis and the development of epilepsy.
Deep Dive:
In acquired epilepsies, a brain injury following head trauma or status epilepticus (a prolonged seizure) can be followed by a latent period called epileptogenesis. During this period, seizures are not occurring, but the brain is undergoing many changes that render it susceptible to seizures [1]. Scientists want to better understand what happens in the brain during this process with the goal of stopping it and ultimately preventing epilepsy. CURE Epilepsy funded two such scientists, Drs. Amy and Audrey Yee (cousins), who focused their research on two cell signaling pathways and changes that take place during epileptogenesis [2].
Previous studies have shown that the cellular signaling pathway known as mTOR is widely implicated in some epilepsies [3]. The focus of the current study was to explore both mTOR’s role and biochemical integration with a second biological pathway called the Wnt pathway together as part of the process of epileptogenesis. The Wnt pathway is implicated in cancer [4] so the CURE Epilepsy grant allowed these two cousins to leverage their individual research foci in this innovative study, which led to the discovery of the role Wnt signaling plays in epileptogenesis [2].
For their study, the researchers used two types of mouse models, one in which status epilepticus had been chemically induced and the other in which Wnt signaling had been genetically enhanced. To create a complete picture of the mTOR and Wnt signaling pathways during epileptogenesis, the scientists used state-of-the-art techniques to examine the levels of mRNA (molecules that carry the genetic code for protein) and the relevant proteins themselves, including where in the brain they are expressed. The scientists also looked at the balance of chemical messengers known as neurotransmitters [2] and focused on an area of the brain called the hippocampus because of its role in seizure generation and propagation [5].
The researchers first showed that epileptogenesis was associated with activation of the Wnt and mTOR signaling pathways. Next, they investigated the basis for enhanced signaling through these pathways and found that there were accompanying changes associated with the way glucose is metabolized in brain cells during epileptogenesis. The changes in the way glucose is metabolized were also associated with an altered balance of neurotransmitters in the brain. Finally, the investigators showed that Wnt signaling is critical to epileptogenic changes that produce seizures. Using the genetically modified mice with enhanced Wnt pathway activation, they found enhanced seizure susceptibility (that is, the mice had stronger seizures) through the same processes described above [2].
This study demonstrates the interaction between the mTOR and Wnt pathways in epileptogenesis, which was previously unknown. By combining knowledge from the fields of cancer and epilepsy, Drs. Amy Yee and Audrey Yee were able to use cross-disciplinary techniques to better understand epileptogenesis. The hope is that by better understanding changes in the Wnt and mTOR pathways following a brain injury, scientists can create safe therapeutic approaches that can be used during the epileptogenic period to prevent epilepsy. Notably, the mechanisms elaborated by these investigators also have implications for genetic epilepsies, such as tuberous sclerosis complex in which the mTOR pathway is disrupted [6]. Thus, the findings from this study may have significant implications for genetic epilepsies as well.
Research to define the processes that happen during epileptogenesis is critical to the discovery of better therapeutic strategies to prevent epilepsy following a brain injury. This CURE Epilepsy-funded study revealed that changes in the Wnt and mTOR signaling pathways, and the changes in glucose metabolism and neurotransmitter balance may lead to the progression of epileptogenesis and the development of epilepsy [2]. While further research is needed to define these changes in detail, this study provides hope that targeting the mTOR and Wnt pathways by medications such as sirolimus (rapamycin) or specific inhibitors of the Wnt pathway may be effective in halting the progression of epileptogenesis.
Literature Cited:
- Lukawski, K. et al. Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies. Pharmacol. Rep. 2018; 70(2): 284-293.
- Alqurashi, R.S. et al. A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis. PLoS One 2021; 16(8): e0252282.
- Meng, X.F. et al. Role of the mTOR signaling pathway in epilepsy. J Neurol Sci, 2013; 332(1-2): 4-15.
- Zhan, T., Rindtorff, N. and Boutros, M. Wnt signaling in cancer. Oncogene 2017; 36(11): 1461-1473.
- Avoli, M. The epileptic hippocampus revisited: back to the future. Epilepsy currents, 2007. 7(4): p. 116-118.
- Curatolo, P. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr. Neurol. 2015; 52(3): 281-289.