ENDOAMPAR · Endosomal sorting of AMPA receptors for synaptic plasticity

Synaptic connections in the brain are continuously remodelled in response to neuronal activity. This process, known as synaptic plasticity, is widely seen as the cellular correlate of learning and memory. Hence, it is expected that the elucidation of the mechanism underlying synaptic plasticity will help to understand the pathological alterations that result in cognitive deficits.It is being increasingly appreciated that synaptic transmission can be modulated by postsynaptic membrane trafficking events, which include the insertion and removal of neurotransmitter receptors, such as AMPA-type glutamate receptors, at synapses in response to neuronal activity. These processes are critical for some forms of synaptic plasticity, such as long-term potentiation (LTP) or long-term depression (LTD). However, the mechanisms controlling membrane trafficking at the postsynaptic terminal and its connection to synaptic plasticity are far from clear.The small GTPase Rab5 is a mediator of protein transport from membrane to early endosomes. More specifically, Rab5 removes AMPA receptors from synapses in an activity-dependent manner and this event is necessary and sufficient for LTD. The goal of this project is to study the role of Rab5 effectors APPL1, WDFY2 and EEA1 in the endocytosis of AMPA receptors during synaptic plasticity. Previous work suggest that APPL1 may act as an early sorting station, while phosphoinositides and Rab5 control the divergent trafficking towards EEA1 or WDFY2 endosomes. In this proposal we will evaluate whether these components of the endosomal machinery organize AMPA receptor trafficking in the specialized environment of the postsynaptic terminal during plasticity. To this end we will use a combination of electrophysiology, molecular biology and imaging on brain tissue. We hope that the elucidation of these basic mechanisms of synaptic function will help us to understand the alterations of synaptic plasticity associated to some mental disorders.