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Grenoble Institut des Neurosciences Grenoble Institut des Neurosciences

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Dysfunction of GABAergic Cholecystokinin-expressing basket cells induces hyperexcitability in the hippocampus of a transgenic mouse model of Alzheimer disease

Objectifs

We will investigate how cytosolic accumulation of amyloid-? oligomers (A?o) in GABAergic Cholecystokinin-expressing basket cells (CCKs) induces synaptic alterations in this subtype of interneuron.
 

Résumé

CCKs interneurons are activated by glutamatergic neurons located in CA3 region of the hippocampus. This transmission depends on two glutamatergic receptors, NMDA and AMPA. We have recently shown in neurons that subsequently to Amyloid precursor protein (APP) processing, a pool of A?o accumulates inside the cytosol inducing the loss of NMDA receptor function. It has been shown that conversely to other interneurons subtypes almost all CCKs are APP positive. Thus APP processing and A?o accumulation in this subtype could significantly alter NMDA receptor function and by consequence synaptic plasticity potential. In contrast to paravalbumin-expressing basket cells in which AMPA receptors are mainly composed by GluA4 subunits that confer calcium permeability, CCKs contain AMPA receptors that are typically comprised of GluA2/3 heteromers preventing any calcium permeability. It has been demonstrated that neuronal response to a cytosolic accumulation of A? oligomers was the rapid switch in AMPA receptors subunits conferring calcium permeability. Therefore, a switch in AMPA receptor subunits followed by calcium permeability in CCKs could cause severe modifications of synaptic plasticity mechanisms as well as toxicity.
 

Méthodes

CCKs are located in the stratum radiatum with a well characterized electrophysiological signature of fast spiking interneurons. Thus, in order to evaluate AMPA and NMDA receptor function in CCKs we will perform patch clamp experiments. Modification of NMDA receptor expression as well as a changed in AMPA receptor subunits composition will be analyzed by Western Blot and immunofluorescence.
 

Références

  • Rolland M et al; Effect of A? oligomers on neuronal APP triggers a vicious cycle leading to the propagation of synaptic plasticity alterations to healthy neurons. Journal of Neuroscience 22 May 2020, JN-RM-2501-19
  • Bosson A et al; TRPA1 channels promote astrocytic Ca2+ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-? peptide. Mol Neurodegener. 2017 Jul 6;12(1):53.
  • Frandemiche ML et al ; Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers. J Neurosci. 2014 Apr 23;34(17):6084-97

Domaines d'expertise requis

Electrophysiology, Confocal microscopy, Molecular Biology, Immunofluorescence.

Contacts

F. Lanté, MCF UGA
Email : fabien.lante@univ-grenoble-alpes.fr
 

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Mise à jour le 26 juin 2020

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