Study design regulating postsynaptic expression of AMPA receptors. AMPA receptors (AMPAR) are stabilized at the PSD by GRIP1 proteins. Binding of glutamate neurotransmitters allows lateral diffusion of AMPAR. The serine S880 of the GluA2 subunit is phosphoryled by PKC. This change increases its affinity to PICK1 protein. In the endocytic vesicles (EV), AMPAR subunits are ubiquitinated by UBE3 ligase RNF167. Following endocytosis, AMPARs are found in early endosomes (EE). A loss of ubiquitination allows membrane recycling of receptors via recycling endosomes (RE). Ubiquitinated AMPAR are trafficked to lysosomal degradation via late endosomes (LE).

Synaptic functional changes can lead to loss of plasticity and consequently alter the storage of information in the brain. Examples include Alzheimer’s disease, which affects the synaptic expression of AMPA-type glutamate receptors (AMPAR), and schizophrenia, which has abnormal regulation of glutamate receptor activity including AMPARs. AMPARs are ionotropic receptors that mediate the majority of fast excitatory neurotransmission in the central nervous system. The synaptic expression of AMPARs is controlled by several factors such as endocytosis, recycling and lysosomal degradation. Several recent studies have shown the importance of post-translational modifications such as phosphorylation and ubiquitination in the synaptic regulation of these receptors. Ubiquitination is an enzymatic process resulting in the covalent addition of a small molecule ubiquitin to a substrate such as AMPARs. In addition, AMPARs can be phosphorylated by different kinases such as PKC, PKA and CaMKII. The goal of this project is to dissect the crosstalk between phosphorylation and ubiquitination in order to better understand their roles in the regulation of AMPARs. We hope that our work will help find the right treatments for Alzheimer’s disease or schizophrenia.

Name: Layal El Cheikh Hussien, B.Sc
Supervisor: Marc Lussier (UQAM)
Laureate: Master fellowship 2019