CURE Grantee Dr. Janice Naegele of Wesleyan University has been working on harnessing the brain’s own inhibitory power as a treatment to reduce excitability and “quiet” the overly excitable epileptic brain. As a promising first step, she and her team have successfully shown that transplantation of mouse inhibitory neurons into the mouse hippocampus – a brain structure that is often involved in epilepsy – can reduce the number of seizures in mice with temporal lobe epilepsy. (1)
Temporal lobe epilepsy is the most common form of epilepsy, with neuronal loss being one of its hallmark traits. (2,3) The loss of inhibitory neurons can be an important factor in the development or worsening of the disorder, (4) because the balance between excitatory and inhibitory neuronal activity is essential for proper brain function. Fewer inhibitory neurons can decrease inhibitory neurotransmission, in turn leading to excessive neuronal excitation, seizures, and epilepsy. One focus of Dr. Naegele’s epilepsy research has been to find a way to increase inhibition in the hyperexcitable epileptic brain. (5)
Dr. Naegele used her CURE grant to focus on transplanting both mouse and human inhibitory neurons into the hippocampus of mice with temporal lobe epilepsy. She hypothesized that these inhibitory neurons would wire up with existing neurons, increasing inhibitory transmission and decreasing the hyperexcitability that characterizes temporal lobe epilepsy. This type of treatment is called “regenerative medicine” because it uses healthy tissue to restore normal brain functioning. An advantage of regenerative medicine is that the transplanted cells can potentially replace lost or damaged inhibitory neurons and also integrate into the existing brain circuitry. This treatment would provide a cure for seizures by addressing the root cause, unlike standard antiepileptic drugs that simply treat the symptoms of seizures.
Indeed, as shown by advanced imaging techniques, the inhibitory neurons Dr. Naegele’s team transplanted into the brains of mice with temporal lobe epilepsy formed new, functional connections with excitatory neurons already present in the hippocampus, providing the increased inhibition that likely led to fewer seizures in these mice. (1)
Following the success of quieting seizures using the implantation of mouse inhibitory neurons, Dr. Naegele and her team are now focused on a means to quiet seizures by implanting human inhibitory neurons, pushing this research one step closer to being a viable treatment for people with epilepsy. As part of their strategy, they are keeping in mind important potential differences in neuronal generation and transmission between humans and mice. (6)
Dr. Naegele’s research brings an exciting possibility to the future of epilepsy treatment: the transplantation of a type of neuron that already exists in the human brain with the goal of stopping seizures. While work still remains, CURE applauds the progress Dr. Naegele has made thus far. We share Dr. Naegele’s hopes that her approach becomes a non-drug method of treating those affected by not only temporal lobe epilepsy, but other forms of epilepsy as well.
1 Henderson et al. Long-term seizure suppression and optogenetic analysis of synaptic connectivity in epileptic mice with hippocampal grafts of GABAergic interneurons. J Neurosci 2014; 34(40):13492-13504.
2 Pitkänen A, Sutula TP. Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Neurol 2002; 1(3):173-181.
3 Engel J Jr, Williamson PD, Weiser HG. Mesial temporal lobe epilepsy. In: Epilepsy: a comprehensive textbook (Engel J Jr, Pedley TA, eds) 1997: 2417-2426.
4 Kumar SS, Buckmaster PS. Hyperexcitability, interneurons, and loss of GABAergic synapses in entorhinal cortex in a model of temporal lobe epilepsy. J Neurosci 2006; 26(17):4613-4623.
5 Van Zandt MA, Naegele JR. GABAergic synapse dysfunction and repair in temporal lobe epilepsy. (2017) Synaptic Plasticity Thomas Heinbockel, IntechOpen; DOI: 10.5772/67218. Available from: https://www.intechopen.com/books/synaptic-plasticity/gabaergic-synapse-d….
6 Naegele JR. Controversial brain study has scientists rethinking neuron research. (2018) Available from: https://theconversation.com/controversial-brain-study-has-scientists-ret…