Unveiling the Functional Role of KCC2 and hyperpolarising inhibition in the Maturation of Cortical Circuits.

The NeuroSchool PhD Program of Aix-Marseille University (France) has launched its annual calls for PhD contracts for students with a master's degree in a non-French university. 

This project is one of the proposed projects. Not all proposed projects will be funded, check our website for details.

State of the art: Perinatal cortical networks generate discontinuous, synchronized bursts that later desynchronize into continuous, statedependent activity (Minlebaev M, Ben-Ari Y, Khazipov R.; doi: 10.1152/jn.00759.2006). Early GABAergic signalling can be depolarizing because neurons have elevated intracellular Cl-, maintained by NKCC1 and limited KCC2; developmental KCC2 upregulation shifts E_GABA negative and strengthens inhibition (Rivera et al.,1999; DOI:10.1038/16697). Our recent work shows that some perinatal interneuron classes already express functional KCC2 and hyperpolarizing GABA (Szrinivasan et al., Nat Commun 2025; doi: 10.1038/s41467-025-67270-x). Early-recruited dendritetargeting SST interneurons can regulate synchrony and sensory processing (Tuncdemir et al., 2016). We test whether SST-cell KCC2 drives the burstto-continuous transition and yields an electrophysiological signature.  

Objective : Define when SST interneurons acquire functional KCC2 and how this relates to their maturation and recruitment during spontaneous activity. (2) Test circuit consequences of SST-specific KCC2 disruption (excitation–inhibition balance, synchrony, sensory-evoked processing). (3) Derive in vivo electrophysiological signatures of altered Cl− homeostasis and evaluate normalization by acute KCC2 modulation. 

Methods: Sst-Cre x conditional Slc12a5 (KCC2) mice; validation by genotyping and KCC2/SST immunohistochemistry. In vivo laminar siliconprobe recordings in developing somatosensory cortex (spontaneous and whisker-evoked activity). Gramicidin-perforated recordings for E_GABA/Cl- driving force; acute KCC2 modulation; targeted transcriptomics/qPCR. Burst/oscillation metrics and machine-learning classifiers for biomarker extraction. 

Expected results: A developmental timeline linking SST-cell KCC2 function to the switch from bursty to continuous cortical activity.Causal evidence that impaired SST-cell KCC2 destabilizes inhibition, amplifies synchrony, and alters sensory responses. A compact set of biomarkers for early inhibitory dysfunction and initial proof-of-principle pharmacological rescue. 

Feasibility:Established pipelines for neonatal surgery/in vivo recordings and KCC2 assays. Animal work will comply with EU Directive 2010/63/EU and is covered by a French APAFIS authorization (APAFiS#38335). 

Complementarity of two PIs (co-supervision):  PI Marat Minlebaev: developmental in vivo electrophysiology and early cortical activity analysis. PI Claudio Rivera: chloride homeostasis/KCC2 biology with molecular tools and functional modulation (imaging, opto/chemogenetics, pharmacology). 

Within Aix Marseille Université, NeuroMarseille brings together 8 research laboratories and NeuroSchool, a graduate school in neuroscience, to increase the attractiveness of the university, international collaborations, interdisciplinarity, links with the clinical and industrial worlds and the integration of students into professional life. 

Launched in July 2018, NeuroSchool unifies and harmonizes the training of the third year of the Bachelor of Life Sciences (Neuroscience track), the Master's and the PhD in Neuroscience. 

• Expected candidate profile :

1.  Rodent handling; motivation for neonatal surgery/in vivo recordings.
2. Electrophysiology and signal processing (LFP/spikes; sensory paradigms).
3.  Programming (Python/Matlab/R) plus statistics/ML for time-series data.
4.  Molecular neurobiology basics (genotyping, immunohistochemistry; qPCR/RNA).