Rab-GTPase-mediated sorting and compartmentalization of AMPA receptors during hippocampal synaptic plasticity

The physiological changes that occur at synaptic connections between neurons in response to alterations in neuronal activity, a process known as synaptic plasticity, is generally understood as the neurobiological basis for learning and memory processes. The hippocampus is an important brain region for the encoding of learning episodes and is the unfortunate target of several neurological diseases. In the hippocampus, the constitutive and regulated trafficking of AMPA-type glutamate receptors (AMPARs) dominates excitatory synaptic transmission. AMPARs are tetrameric and mostly heteromeric structures formed by specific combinations of the AMPAR subunits GluR1-4. GluR2/GluR3containing receptors are constitutively cycled into and out of synaptic membranes in an activity-independent manner and modulate basal AMPAR-mediated transmission. Activity-dependent synaptic plasticity paradigms, such as long-term potentiation (LTP), result in the regulated insertion of GluR1/GluR2-containing receptors into spines and synaptic surfaces and subsequent up-regulation of GluR2/1GluR3-containing receptors to maintain adequate synaptic scaling of AMPA transmission for future plasticity events. In contrast, the activity-dependent removal of both GluR1/GluR2 and GluR2/GluR3-containing receptors leads to a long-term depression (LTD) in hippocampal synapses.; The members of the Rab family of small GTPases are critical regulators of intracellular membrane trafficking and sorting in eukaryotes. Previous work has shown that multiple Rab proteins are present in axonal and dendritic regions of hippocampal neurons; therefore, we proposed that Rab proteins may be involved in trafficking of AMPARs in to post-synaptic spines of the hippocampus. We have found that at least four distinct Rab-dependent endosomal sorting processes are required for the bidirectional movement of AMPARs within the post-synaptic terminal. This conclusion is based on electrophysiological data monitoring functional endogenous receptors at synapses, and fluorescence imaging experiments to visualize the partition of AMPARs between dendritic and spine compartments after plasticity induction. Based on this information, we now propose an ordered sequence of Rab5-, Rab4-, Rab11- and Rab8-dependent membrane trafficking events for the local sorting of AMPARs at postsynaptic terminals during plasticity. The results presented in this work constitute the first molecular and anatomical dissection of the local endosomal network that mediates AMPAR trafficking during synaptic plasticity.