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A closer look at brain inhibition and epilepsy following prenatal X-ray exposure

Context

The risks posed to the developing fetus in case of radiotherapy treatment to the mother are still insufficiently identified. This may result in an inadequate cancer treatment, the avoidance of radiotherapy or termination of the pregnancy. Hence, a better understanding of radiation-induced defects to the developing embryo is warranted, taking into account the different cell types and developmental processes that occur within the developing brain. Indeed, the effect of radiation on the development and differentiation of so-called interneurons or inhibitory neurons has so far been neglected, despite epidemiological indications of a disturbed interneuron function following in utero radiation.

This project relies on ongoing and very successful collaborations with Prof. Dr. Bert Brône (UHasselt), expert in cellular control of brain development and electrophysiology, with Prof. Dr. Eve Seuntjens, expert in interneuron development and with Prof. Dr. Ilse Smolders (VUB), expert in epilepsy research. As such, novel techniques for SCK•CEN will be acquired during this PhD thesis, e.g. patch clamp electrophysiology, recordings of epileptic discharges and in utero electroporation, while this will also spark new and exciting possibilities and research opportunities. Moreover, the obtained results fit perfectly in the research goals of the Radiobiology Unit. Thus, this project will be of interest for the implementation of suitable radioprotection guidelines and to guarantee an adequate follow-up of in utero exposed individuals at risk for adverse health effects and brain disorders.

State of the art

Epidemiological studies as well as animal experiments have helped us understand some of the possible dangers of in utero exposure to ionizing radiation. Particularly with regards to the central nervous system (CNS), week 8-15 and to a lesser extent week 16-25 of human pregnancy has been defined as the most radiosensitive period. By week 8, the development of the major organs has been completed, while the CNS is still undergoing key developmental processes such as neuronal proliferation, migration and differentiation, which explains its high sensitivity to radiation-induced damage. To better understand these radiation-induced defects, which include microcephaly and mental retardation, animal studies have proven extremely helpful, but there are still a lot of knowledge gaps and questions remaining. For instance, while most research has focused on excitatory neurons, data about possible radiation-induced changes in inhibitory interneurons are scarce. Yet, these type of neurons play an indispensable role in brain development, maturation and wiring of the brain, and are importantly involved in cognition.

Besides mental retardation and microcephaly, in utero exposed atomic bomb survivors also displayed an increased prevalence of seizures and epilepsy [1], which is defined by a hyper-excitability of the neuronal network and a concomitant imbalance in inhibitory signaling [2]. In other words, seizures/epilepsy can occur due to imbalances in the inhibitory control of interneurons on excitatory neurons, and may be associated with an improper interneuron development, integration and/or functionality. Although little animal research has been performed to investigate the possible underlying causes of radiation-induced epilepsy, such as a defective interneuron development and functioning, in utero exposure of E17 rats to moderate/high doses of irradiation (145-225 cGy) is often employed as a model for cortical dysplasia associated with microcephaly. This model often displays both spontaneous and interictal (subclinical) epileptiform discharges and seizures, which is believed to occur through a disordered interneuron migration and a significant loss of interneurons, accompanied by a reduced inhibitory synaptic activity and spontaneous firing [3-7]. Radiation-induced loss of neocortical interneurons in these rats was more pronounced than that of excitatory neurons, indicating a reduced capacity of interneurons to recover from radiation-induced injury compared to excitatory neurons [8]. Furthermore, unpublished data from the Radiobiology Unit showed that prenatal irradiation (0.1 and 1.0 Gy) resulted in cell death not only in the dorsal neocortex, but also in the ganglionic eminences (GEs) and the lateral pallium, respectively the birthplace of the majority of interneurons and the region via which they migrate to the neocortex. Moreover, others have observed differences in the radiation sensitivity between excitatory and inhibitory progenitors, in that the levels of cell death were more pronounced in the GE compared to the neocortex [9]. This might in turn result in a reduction of the number of interneurons eventually populating and integrating within the cortex, leading to seizures and epilepsy or other functional disorders related to an imbalanced inhibition, including attention deficits, working memory decline or psychiatric disorders.

In all, the knowledge on the potential links between prenatal radiation exposure and a defective brain inhibition, with associated risks for e.g. seizures or epilepsy, is extremely scarce. While epidemiological evidence from A-bomb survivors was put forward, experimental data and knowledge on the underlying mechanisms is missing, urging the need for a more detailed investigation using animal models. With this PhD project, we will provide answers to these unprecedented but important research questions using the mouse as a model system. In particular, we will build on our previously obtained data that already show an aberrant neocortical development and functionality of excitatory neurons and that suggest a disrupted interneuron development in response to early prenatal irradiation.

Research hypothesis

In this project, we will test the hypothesis that prenatal radiation exposure increases the risk of developing seizures and epilepsy through a disrupted development, function and functional network integration of inhibitory interneurons. Our research question will benefit from a multidisciplinary team and a waiver of methodologies, ranging from molecular and cellular read-outs to functional tests. This will provide an answer as to whether a defective brain inhibition is the major cause for radiation-induced epilepsy, and whether this originates from defects in brain development.

References

1.            Dunn, K., et al., Prenatal exposure to ionizing radiation and subsequent development of seizures. Am J Epidemiol, 1990. 131(1): p. 114-23.

2.            Kumar, S.S. and P.S. Buckmaster, Hyperexcitability, interneurons, and loss of GABAergic synapses in entorhinal cortex in a model of temporal lobe epilepsy. J Neurosci, 2006. 26(17): p. 4613-23.

3.            Kapur, J., Disordered migration of interneurons within focal cortical dysplasia. Epilepsy Curr, 2006. 6(3): p. 96-8.

4.            Akakin, D., et al., Reduced densities of parvalbumin- and somatostatin-expressing interneurons in experimental cortical dysplasia and heterotopia in early postnatal development. Epilepsy Res, 2013. 104(3): p. 226-33.

5.            Lin, D. and S.N. Roper, Chapter 58 - in utero irradiation as a model of cortical dysplasia. Models of Seizures and Epilepsy (Second edition), 2017: p. 877-885.

6.            Roper, S.N., S. Eisenschenk, and M.A. King, Reduced density of parvalbumin- and calbindin D28-immunoreactive neurons in experimental cortical dysplasia. Epilepsy Res, 1999. 37(1): p. 63-71.

7.            Zhu, W.J. and S.N. Roper, Reduced inhibition in an animal model of cortical dysplasia. J Neurosci, 2000. 20(23): p. 8925-31.

8.            Deukmedjian, A.J., et al., The GABAergic system of the developing neocortex has a reduced capacity to recover from in utero injury in experimental cortical dysplasia. J Neuropathol Exp Neurol, 2004. 63(12): p. 1265-73.

9.            Etienne, O., et al., Variation of radiation-sensitivity of neural stem and progenitor cell populations within the developing mouse brain. Int J Radiat Biol, 2012. 88(10): p. 694-702.

10.          Cho, S.J., et al., Zebrafish as an animal model in epilepsy studies with multichannel EEG recordings. Sci Rep, 2017. 7(1): p. 3099.

University UHASSELT
Phd started on

Mentor

Quintens Roel

Promotor

Brône Bert

Candidate

Berden Lisa

Before applying, please consult the guidelines for application for PhD