Epilepsia Open^® Prize 2018 Basic Science

Read the winning article “Disrupted female estrous cyclicity in the intrahippocampal kainic acid mouse model of temporal lobe epilepsy”: http://onlinelibrary.wiley.com/doi/10.1002/epi4.12026/full

An interview with Jiang Li, 2018 Epilepsia Open Prize Winner for Basic Science Research

Who are you?

I am a Ph.D. student in the Neuroscience Program at the University of Illinois at Urbana-Champaign. Before coming to the U.S., I received my bachelor’s degree in Environmental Science and Engineering from Tongji Universtiy, Shanghai, China. During my undergraduate research, I participated in a study about the neurotoxicity of mercury, an environmental pollutant, where I discovered my interest in neuroscience research. In 2015, I joined Dr. Catherine Christian’s lab to investigate the etiology of reproductive endocrine disorders comorbid with epilepsy.

What got you interested in epilepsy research?

During my interview with Dr. Catherine Christian, the complexity of studying epilepsy impressed me. I was surprised by the fact that epilepsy patients have a higher chance of developing reproductive endocrine issues than the general population. For instance, a higher prevalence of polycystic ovarian syndrome is found among the epileptic population. I would never have realized that epilepsy could have a profound effect on physiological functions outside the central nervous system. Later I learned that epilepsy is associated with many types of comorbidities and these comorbid conditions can affect seizure severity. For example, catamenial epilepsy patients may show a prolonged period of seizure exacerbation when they have menstrual disorders. Therefore, understanding the reproductive endocrine disorders comorbid with epilepsy can benefit seizure control. This idea fascinated me and put me on the path to epilepsy research.

Explain for our general readership what question your study addressed and how did you go about designing your study?

Comorbid reproductive endocrine issues are common among women with epilepsy. However, the etiology of this comorbidity is still understudied. The hypothalamic-pituitary-gonadal (HPG) axis controls reproductive endocrine functions. Disruption of HPG axis function in both patients with epilepsy and animal models of epilepsy have been reported, including changes in sex steroid levels, the collapse of reproductive cycles, and cystic ovaries in a rat model of temporal lobe epilepsy (TLE). We are interested in determining the effects of epilepsy on the hypothalamic neural control of reproduction and identifying whether rescuing HPG axis function could reduce seizure severity. A mouse model of TLE would be ideal for our studies because more tools for investigating and manipulating the neural control of reproduction are available for mice.

The intrahippocampal kainic acid (KA) model of TLE has been commonly used for more than 30 years. It recapitulates the TLE pathological hallmarks and electrographic seizure activities. However, changes in the reproductive endocrine function in the intrahippocampal KA female mouse model of TLE had not been demonstrated before. In this study, we characterized the phenotype, time course, and the prevalence of the reproductive cycle (estrous cycle) disruption in mice after receiving intrahippocampal KA injection. We assessed these properties by performing daily observation of mice estrous cycle stages. We also examined the ovary morphology for evaluating the level of reproductive endocrine disruption at the gonad level.

What were the results and how do you interpret your findings?

We found that mice developed estrous cycle disruption around 2 months after intrahippocampal KA injection. KA-treated mice showed increased time spent in diestrus (a sexually non-receptive period) and less time spent in estrus (the sexually receptive period). The lengths of the estrous cycles were prolonged, mainly due to the continuous diestrus. The estrous cycle disruption was not accompanied by major ovarian pathology, indicating that the irregular cycles may arise from alterations in neural control. Our study provides the first evidence that a local insult targeting hippocampus could result in the long-term development of disrupted estrous cycles in a mouse model of TLE. Therefore, this model can be used for investigating the neural mechanisms linking epilepsy and reproductive endocrine disorders.

What next steps in epilepsy research are you taking and what are your career goals?

Gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus exert neural control for reproduction. Therefore, we are currently studying the activity of GnRH neurons using this mouse model of TLE. Electrophysiological recording of GnRH neurons will reveal whether the GnRH neuron function is changed by epilepsy and whether the change is associated with the development of disrupted estrous cycles. The potential neural mechanisms for GnRH neuron pathology will provide important therapeutic targets for treating reproductive endocrine disorders comorbid with epilepsy. Electroencephalography (EEG) of this model could reveal the relationship between seizure burden, estrous cycle disruption, and GnRH neuron pathology, thus providing important references for seizure management. Our goal is to reduce seizure severity by maintaining the HPG axis function through the control of GnRH neuron activities.

The next step in my career path is to advance my knowledge and experience in epilepsy research through postdoc training. In the long term, I would like to become an independent investigator at a research institute, focusing on studies about epilepsy.

What does the Epilepsia Open Prize mean for you, your laboratory, research institute, and your future?

It is my honor to receive the 2018 Epilepsia Open Prize. As a Ph.D. student, I am grateful that my enthusiasm for epilepsy research has been greatly supported and recognized. My future academic career will be greatly enhanced with the support from Epilepsia Open Prize. This prestigious prize is also an honor for our laboratory, and we hope that more attention will be given to the importance of reproductive endocrine disorders comorbid with epilepsy through this prize and our research. Investigating the relationships between reproductive endocrine function and seizures also emphasizes the importance of sex differences in epilepsy. As a woman in science, I feel proud that our study will greatly support women with epilepsy and Epilepsia Open Prize is the best proof for our contributions. I would like to express my deepest gratitude to Dr. Catherine Christian for guiding me into the epilepsy field by this wonderful project. Last but not least, this prize provides evidence of the significant contributions from the University of Illinois at Urbana-Champaign to epilepsy research.

Aristea Galanopoulou, Dieter Schmidt, and Xuefeng Wang
Editors-in-Chief, Epilepsia Open