The human brain is the most complex organ we know, made up of billions of interlinked neurons forming intricate networks. Information in the form of electrical signals travels these networks allowing us to feel, move, and think. However, in some cases, these complex networks can be incorrectly formed, resulting in aberrant signaling. In epilepsy, neuron misfiring causes epileptic seizures that can be life-threatening. 

Epilepsy can have many reasons, including genetic mutations. In the last few years, the Knoblich lab has been studying Tuberous Sclerosis, a rare type of childhood epilepsy caused by mutations in the TSC2 gene. Using patient-derived brain organoids – stem cell-based models that recapitulate the development and function of the human brain – the team identified a type of human-specific neuronal progenitors, as the culprits behind this disease. The team showed that CLIP cells produce the tumor-like protrusions (tubers) responsible for epileptogenic signaling. However, what kind of neurons these progenitors produce, and how these neurons cause aberrant electrical signaling, is still unknown. 

Olena Kim’s project focuses on studying what types of neurons these progenitor cells give rise to, how these neurons integrate within the brain’s existing neuronal circuits, and how mutations in the TSC2 gene affect their function. “I will use patient-derived cells to produce organoids that model a normal brain and one carrying a TSC2 mutation,” explains Kim. “By comparing both models, I’ll identify differences in how new neurons function and interact within the brain.” 

For this, Kim will leverage advanced electrophysiology techniques to measure electric activity within a single cell and how it is transmitted from one neuron to another within a neural circuit. “I’ll be able to study the intrinsic properties of these neurons, but also how they fit – or don’t – within the bigger network,” Kim says. 

To better understand the mechanistic differences between normal and TSC2-mutant neurons, Kim will use advanced electron microscopy to study whether TSC2 mutations affect the structure of the synapsis – the connection between neurons essential to signal transmission – and whether these alterations could explain the aberrant electrical signaling present in Tuberous Sclerosis. 

“Tuberous Sclerosis is a very interesting case study, because usual anti-epileptic drugs can’t treat it. This means that the epileptogenic mechanisms in this disease are unique,” Kim says. “Understanding how TSC2-mutated neurons cause this type of epilepsy could reveal new mechanistic insights into how the brain’s connections are formed. This could be the first step to identifying druggable targets and, eventually, developing a therapy for this disease.” 

About Olena Kim 

Olena Kim earned her PhD at the Institute of Science and Technology Austria (ISTA) in 2022, where she studied the molecular mechanisms behind synaptic transmission between neurons. In 2023, she joined the lab of Jürgen Knoblich at IMBA as a postdoctoral fellow.

 
About the APART-MINT Fellowship 

APART-MINT is a funding program by the Austrian Academy of Sciences (ÖAW) aiming to support excellent young scientists in mathematics, natural and life sciences, technical sciences and medicine in the first post-doc phase of their careers. The fellowships, with a duration of 12 months, are intended to support unconventional, innovative, potentially risky ideas with an uncertain outcome.