The light chain of MAP1B: a novel modulator of AMPA receptor trafficking in hippocampal neurons

Resumen

The strength of synaptic transmission in the brain relays largely on the controlled addition and removal of neurotransmitter receptors to and from synapses. AMPA-type glutamate receptors (AMPARs) mediate the vast majority of excitatory transmission in the mammalian central nervous system. Their regulated trafficking has been proposed to be one of the major mechanisms underlying the expression of synaptic plasticity at hippocampal synapses. In this work, we have explored the potential role of a microtubule-associated protein, MAP1B, in the fine-tuning of AMPAR trafficking in CA1 hippocampal neurons. Using a combination of molecular tools, electrophysiology and confocal microscopy, we reveal a novel role of the light chain of MAP1B (MAP1B-LC) as a key player in the subcellular sorting of a specific population of AMPARs. We demonstrate that MAP1B-LC over-expression results in a net reduction of the mobile population in dendrites and their accumulation in spines of recombinant GluA2 AMPARs, whereas the dendritic trafficking and delivery to spines of recombinant GluA1 AMPARs is unaltered. Indeed, we show that MAP1B-LC targets specifically the endogenous GluA2-GluA3 population of AMPARs, as their constitutive cycling toward synapses is impaired upon MAP1B-LC over-expression and consequently, basal synaptic transmission is decreased. We also demonstrate that the dendritic targeting of GRIP1, a specific interactor of GluA2/GluA3 subunits that also binds MAP1B-LC, is altered in the presence of enhanced levels of MAP1B-LC. Using deletion mutants of MAP1B-LC, we conclude that MAP1B-LC binding to GRIP1 together with its ability to interact with microtubules is essential to regulate the surface expression and presence at synapses of the GluA2-GluA3 population of AMPARs, and consequently, the degree to which they contribute to basal synaptic transmission in CA1 hippocampal neurons. Importantly, the model we propose assigns a functional meaning to the interaction between MAP1B-LC and GRIP1 for the first time.