Investigating the role of plasticity at excitatory synapses onto interneurons in memory processing – EXINmemory

The importance of GABAergic interneurons (INs) in orchestrating the dynamic of principal cells (PNs) networks especially during cognitive processes such as learning and memory is unanimously accepted. Central to this control are the EX-IN synapses - the glutamatergic synapses onto GABAergic cells - involved in all local inhibitory circuits controlling principal cells activities in various brain states and during cognitive tasks. However, how?, when? and where? plasticity at EX-IN synapses occurs during learning and memory is almost completely unknown. Based on our preliminary data suggesting the occurrence of plasticity at Hippocampus EX-IN Prefrontal cortex synapses during spatial memory processing, and the recent development of versatile functional tools enabling the blockade of synaptic plasticity in a cell-specific manner, we aim to thoroughly characterize EX-IN plasticity events associated with declarative and non-declarative memories.
Our project is separated in three Work-packages (WPs): In WP1, we will study fundamental mechanisms of plasticity at EX-IN synapses in well-defined, genetically accessible GABAergic cells. This will allow defining key mechanisms regulating “prototypical EX-IN synapses” and design tools to manipulate EX-IN plasticity. In WP2, the necessity of EX-IN plasticity in the encoding, consolidation and recall of spatial episodic and contextual fear memories will be tested in vivo by interfering with AMPAR mobility, a necessary step for long term potentiation. In WP3, EX-IN plasticity proxies will be studied in behaviorally-engaged GABAergic cell populations identified using light-based, cell-activity labelling strategies. This will allow determining cellular mechanisms of EX-IN plasticity during learning.
Collectively, these efforts will allow shedding light onto these neglected glutamatergic synapses, and possibly open some new therapeutic ways to control for pathologic forms of memory.