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THE ROLE OF SYNAPSE POLARITY ON THE FORMATION AND PLASTICITY OF INHIBITORY CONNECTIONS

Project description

GABA’s role in early brain development

During early brain development, GABA, typically an inhibitory neurotransmitter in adults, acts as a depolarising signal with crucial effects on synapse formation. However, the role of depolarising GABA in this process remains unclear, particularly in terms of how changes in chloride concentration influence synapse formation. It is also uncertain whether these changes occur alongside synapse development or if they directly drive it. Additionally, the exact mechanisms and locations of these processes across different subcellular compartments have yet to be explored. Supported by the Marie Skłodowska-Curie Actions programme, the SyPoFaPIC project will study the mechanisms of chloride balance and GABAergic synapse formation in living organisms. It will shed light on how these processes unfold across spatial and temporal dimensions.

Objective

In adults, GABA acts as the primary inhibitory neurotransmitter, but during early development, GABAergic synaptic transmission has depolarising effects and can influence various developmental processes. The role of depolarising GABA in synapse formation remains unclear. Specifically, whether changes in intracellular chloride concentration influence synapse formation directly or whether it occurs concomitantly with it is not known. Moreover, the specifics of how and where this process unfolds across different subcellular compartments have not been studied.
Our hypothesis posits that GABAergic synapse formation requires depolarising GABA. Subsequently, an increase in GABAergic transmission promotes the developmental switch in chloride levels, a progression that unfolds spatially and temporally along the dendritic-axonal axis within the cell.
This proposal seeks to elucidate the fundamental mechanisms governing chloride balance and the formation of GABAergic synapses in living organisms. These developmental processes occur across various spatial dimensions with precise timing. The strength of this proposal lies in integrating cutting-edge methodologies to comprehensively describe both the structure and function of the dynamic chloride environment within developing neurons and its impact on the formation, function, and plasticity of inhibitory synapses in vivo. This will be accomplished by implementing an in vivo two-photon chloride imaging approach, together with precise tracing of inhibitory synapse formation over development and following manipulations of either intracellular chloride levels or neuronal network activity.
Disruptions in inhibitory synapses and changes in the timing of the postnatal intracellular chloride shift have been associated with developmental brain disorders. Hence, gaining insights into the principles governing GABAergic synaptogenesis and synapse plasticity will contribute to a better understanding of these pathological mechanisms.

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Topic(s)

Funding Scheme

HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

(opens in new window) HORIZON-MSCA-2024-PF-01

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Coordinator

KING'S COLLEGE LONDON
Net EU contribution
€ 260 347,92
Address
STRAND
WC2R 2LS London
United Kingdom
Region
London Inner London — West Westminster
Activity type
Higher or Secondary Education Establishments
Links
Total cost
No data