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An “exciting” era for epilepsy research?

February 12, 2020
By Alexandros G. Kokkosis, PhD Candidate in the Department of Pharmacological Sciences, Stony Brook University, New York

Helen ScharfmanIt definitely is! That was the immediate response that came up on my mind after attending the keynote lecture by Dr. Helen Scharfman a few months ago at the Pharmacology Graduate Symposium at Stony Brook University. The talk was about new ideas regarding the role of adult-born neurons in the dentate gyrus in health and disease and a significant part of it was focusing on the newly discovered mechanisms in epilepsy research.

Dr. Helen Scharfman is a Professor of Child & Adolescent Psychiatry, Psychiatry, and Physiology & Neuroscience at the New York University School of Medicine, while her laboratory is located at the Nathan Kline Institute for Psychiatric Research at New York. The emphasis of her laboratory is to understand the basic mechanisms of normal function in order to better address dysfunction; i.e., neurological disorders and psychiatric illness.

Later in the day I was fortunate to meet again with Dr. Scharfman and discuss about novel scientific avenues for neurologic disorders in depth, and address questions about the current progress in the field of epilepsy. After all, Dr. Scharfman’s outstanding scientific contribution has been repeatedly recognized by several scientific societies, with the last example being the Research Recognition Award by the American Epilepsy Society in December.

Epilepsy is a chronic and currently incurable neurologic disorder, which affects people of all ages, and the hallmark of which is recurrent, unprovoked seizures.  The pun “exciting” in the title implies to a neuroscientist the neuronal excitation; and the hippocampal dentate gyrus (DG) has been put under the microscope again with the excitatory effects of a specific cell type in it -the mossy cells (MCs)- being implicated in the process of epileptogenesis.

The brain’s hippocampus is defined as areas CA1, CA2, CA3, and the DG. More specifically, the DG is critical to neurogenesis, memory formation, mood regulation, anxiety and other cognitive functions. As a result, it is implicated and vulnerable in diverse neurological diseases and psychiatric disorders, such as Alzheimer’s disease and Epilepsy. “Throughout my research it was always critical for me to understand how the neuronal subtypes and pathways allow them to perform their normal functions and then elucidate how these are disrupted in diseases”, Dr. Scharfman said to explain the research basis of her lab.

“The curiosity about epilepsy first started during my undergraduate years, through my reading for courses I was taking. Of course, it is a horrible disease but on the other side I was fascinated by how a person could suddenly have a seizure and then…just stop. Many years have passed since then, and I strongly believe that this is an exciting time to be conducting epilepsy research. Fortunately, improved and selective methods (such as optogenetics, advanced imaging and recording methods) have provided new opportunities for both empirical and computational approaches”, Dr. Scharfman enthusiastically notes. “However, it is not only the improvement of techniques that renders this era exciting, but also the concepts underlying the epilepsy that are being rigorously updated based on new findings; i.e. the importance of DG to disease pathophysiology as well as the role of glia, inflammation, and diverse aspects of genetics are becoming increasingly appreciated”.

Based on this vital importance of the DG, Dr. Scharfman’s lab recently demonstrated its contribution to seizure transition and epileptogenesis. The major cell types of the DG include the glutamatergic granule cells (GCs), the glutamatergic mossy cells (MCs), and the GABAergic basket cells (BCs). “GCs can receive a strong entorhinal cortical excitatory input and innervate area CA3 by making powerful excitatory ‘‘detonator’’ synapses on the pyramidal cells, rendering the DG a gateway to the hippocampus; the regulation of GC activity is therefore paramount for normal hippocampal function”, Dr. Scharfman explains.

Remarkably, a study from Dr. Scharfman’s lab shows that in normal conditions MCs appear to support GC inhibition through the inhibitory BCs. However, in a mouse model of the initial phase of Temporal Lobe Epilepsy (TLE), MC excitation of GCs increases and becomes robust during severe seizures in status epilepticus (SE), contributing to excitotoxicity and epileptogenesis. “It is promising that our analyses reveal that MC inhibition during SE is antiepileptogenic and can confer significant long-term benefits against chronic epilepsy. In addition, this idea also sheds light on the enigmatic vulnerable nature of mossy cells by supporting the hypothesis that hilar neuronal loss is a precipitating factor in TLE”, Dr. Scharfman noted.

However, in the very next seconds Dr. Scharfman underscores the need to do more in order to understand the underlying mechanisms in patients with TLE. “The evidence we have is primarily from animals, not humans; we still do not know how seizures travel in the brains of patients. We figure that seizures are widespread in all neurons, but it may not really be the case; it may just be what skull electrodes are able to show!” Her conception and hypothesis is built on the assumption that we do not really have every single cell in the brain firing at the same time in seizures. Instead, we have networks that they are hyperactive triggering other networks causing synchronized activity all over; such as the hypersynchronous (HYP) seizure transition of GCs we mentioned before.

“Let us not forget that the DG might not be the only area where these “detonators” exist...and it could be fruitful to focally target these additional sites in epilepsy; either by viral delivery, use of closed-loop silencing, or new methods that are on the horizon”, Dr. Scharfman noted and pointed out that advances in neuroimaging will provide the necessary resolution to recognize the exact input circuits that are affected, with multiple recording sites and prognostic oscillation patterns as markers.

“This will significantly change the way an epilepsy patient is treated; it is going to be an exciting era!”

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