ESR 4 - Shaobo Jia

Hosted at DZNE

ESR4 round

I am Shaobo. I joined the ECMED network as a PhD student in Prof. Dityatev's lab, based at the German Center for Neurodegenerative Diseases (DZNE), Magdeburg. Prior to my PhD studies, I completed a Master's degree in Pekin Union Medical College (Tsinghua University) in China, speciliasing in Neuropharcacology with a focus on drug development for insomnia. In the course of my PhD, my research involves the application of telemetry EEG, immunological and other genetic methods to investigate if removal of the ECM glycans would facilitate epileptogenesis invivo; and if treatments promoting aggregation or preventing proteolyptic degradation of ECM proteoglycans are anti-epileptogenic in vivo.



ECM-associated glycans in epileptogenesis and established epilepsy in vivo

Background

Status epilepticus (SE) changes expression of numerous ECM molecules and ECM degrading proteases and thus may result in remodelling of hyaluronic acid and aggrecan-rich ECM of perineuronal nets associated with fast-spiking interneurons. Our previous data shows that enzymatic removal of hyaluronic acid or heparan sulfates leads to epileptiform activity in vitro. Also it is known that enzymatic digestion of chondroitin sulfates enables developmental plasticity and rearrangement of neural networks and thus may be a key event for formation of hyper-excitable networks.  

Objectives

  Theproject is focused on the roles of ECM glycans during the development of epilepsy (epileptogenesis) and established epilepsy in vivo. ECM molecules together with pre/post synaptic neurons and astrocytes play important roles on neural development, regeneration, synaptic plasticity, neuronal excitability and network activity which are crucial for epileptogenesis. From this prospective, the impact of several ECM glycans will be studied.

· The first objective is to verify if removal of the ECM glycans in the adult mouse brain during epileptogenesis would facilitate epileptogenesis and result in more severe seizures; 

· The second objective is to study if treatments promoting aggregation of ECM proteoglycans or preventing proteolytic degradation of these proteoglycans are anti-epileptogenic in vivo.

· The third objective is to test if modulation of ECM during established epilepsy may open a window for efficient irreversible block of seizures by conventional anti-epileptic drugs.

The outcome of this project, in combination with the results acquired from in vitro studies by ESR5 Antonia Yam and biochemistry/immunohistochemistry data from LIN will lead to a deeper insight into the role of ECM glycans in epileptogenesis and established epilepsy.

Approach

As established animal model of epileptogenesis, we induce SE via intrahippocampal injection of kainic acid in mice, and follow development of spontaneous seizures. We use wireless telemetry system (developed by UCL) to monitor seizures long-term for varying periods before or after the epilepsy phenotype is established. ECM glycans are removed by enzymatic manipulation (e.g. ChABC) or by shRNA expression during epileptogenesis or using knockout mice. We analyze changes in seizure frequency and severity after treatment (up to 21 days) and compare performance of animals in cognitive tasks before and after treatments (pharmacological, immunological and optogenetic). At the end, the animals are sacrificed and brain tissue is collected for immunohistochemistry and biochemical analysis of ECM and synaptic proteins.

Collaborations

LIN provides expertise for biochemical analysis of post-SE changes in ECM molecules and synaptic proteins in all experimental conditions. 

UCL provides expertise for EEG recording, data analysis and necessary support for optogenetics experiments.

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