Plasticity in cortical networks & epilepsy


Our lab explores the pathophysiology of focal epilepsies with a specific focus on the function and plasticit of cortical synapses and networks. Our recent work has focused on alterations of neuronal chloride homeostasis in focal epilepsies and the functional impact of mutations associated with epileptic encephalopathies.

Our aim is to resolve the cellular architecture of epileptic networks an identfy key cellular determinants that could represent novel therapeutic targets for pharmaco-resistant epilepsies.

Currently, our main projects focus on:

The neuronal mechanisms of chloride ion transport: since GABAA receptors are mainly permeable to chloride ions, the currents they carry are directly influenced by transmembrane gradients of chloride in neurons. We study the function and regulation of the chloride/cation co-transporter KCC2, which exerts a major control over these gradients in mature cortical neurons (Chamma et al J Neurosci 2013 ; Heubl et al Nat Comm 2017 ; Otsu et al J Physiol 2020 ; Al Awabdh et al 2022) as well the functional impact of its down-regulation, as observed in most forms of focal epilepsies as well as other neurological and psychiatric disorders (Gauvain et al PNAS 2011 ; Chevy et al J Neurosci 2015 ; Goutierre et al Cell Rep 2019; Simonnet et al Neuropsychopharmacology 2023). Recent work investigated the therapeutic potential of targeting KCC2 in mesial temporal lobe epilepsy, the most frequenf form of focal epilepsy in adults (Donneger et al biorXiv 2023). Ongoing work also explores the functional impact of mutations in the Slc12a5 gene, encoding KCC2, on cortical development and function.            

Regulation of neuronal excitability by Kv2.1 channels: Kv2.1 are required for membrane repolarization after high frequency firing, thereby regulating firing freqeuncy in neurons. Numerous mutations in the KCNB1 gene encoding Kv2.1 channels have recently been identified in patients with encephalopathic epilepsies. These disorders are characterized by genralized brain dysfunction with epileptic seizures and cognitive impairment. We perform integrated and multi-level exploration (from single molecules to neural networks) the mechanisms by which Kv2.1 controls neuronal excitability and how these are affected by mutations. In particular, we implement single molecule imaging techniques to investigate how mutations in Kv2.1 channels impact their diffusion propertie  and clustering in the plasma membrane (Kokolaki et al 2020).   


Experimental approaches

We use a multidisciplinary approach combining:

in vitro (patch clamp, LFP and MEA) and in vivo (telemetric ECoG, intracerebral silicon probes) electrophysiology

• anterograde tracing and genetic expression/suppression using viral vectors

• optogenetics

• optical imaging on live neurons

• super-resolution microscopy (STED/PALM/STORM)

• single molecule tracking using quantum dots

• biochemistry and proteomics