MAP1B Light Chain Modulates Synaptic Transmission via AMPA Receptor Intracellular Trapping

Abstract

The regulated transport of AMPA-type glutamate receptors (AMPARs) to the synaptic membrane is a key mechanism to determine the strength of excitatory synaptic transmission in the brain. In this work, we uncovered a new role for the microtubule-associated protein MAP1B in modulating access of AMPARs to the postsynaptic membrane. Using mice and rats of either sex, we show that MAP1B light chain (LC) accumulates in the somatodendritic compartment of hippocampal neurons, where it forms immobile complexes on microtubules that limit vesicular transport. These complexes restrict AMPAR dendritic mobility, leading to the intracellular trapping of receptors and impairing their access to the dendritic surface and spines. Accordingly, increasing MAP1B-LC expression depresses AMPAR-mediated synaptic transmission. This effect is specific for the GluA2 subunit of the AMPAR and requires glutamate receptor interacting protein 1 (GRIP1) interaction with MAP1B-LC. Therefore, MAP1B-LC represents an alternative link between GRIP1-AMPARs and microtubules that does not result in productive transport, but rather limits AMPAR availability for synaptic insertion, with a direct impact on synaptic transmission. The ability of neurons to modify their synaptic connections, known as synaptic plasticity, is accepted as the cellular basis for learning and memory. One mechanism for synaptic plasticity is the regulated addition and removal of AMPA-type glutamate receptors (AMPARs) at excitatory synapses. In this study, we found that a microtubule-associated protein, MAP1B light chain (MAP1B-LC), participates in this process. MAP1B-LC forms immobile complexes along dendrites. These complexes limit intracellular vesicular trafficking and trap AMPARs inside the dendritic shaft. In this manner, MAP1B restricts the access of AMPARs to dendritic spines and the postsynaptic membrane, contributing to downregulating synaptic transmission.

AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking

“…GRIP1 and liprin α also associate with the motor protein KIF1A [ 75 ], suggesting that GRIP1 can interact with more than one motor protein. Indeed, GRIP1 has also been shown to bind the light chain of microtubule-associated protein (MAP) 1B, an interaction required for dihydroxyphenylglycine (DHPG)-induced AMPAR internalization and regulating its trafficking towards the dendrite [ 76 , 77 ].…”

MAP1B mutations cause intellectual disability and extensive white matter deficit

“…LC1 has functions independent of the HC and separate from its role during neuronal development 31 . For instance, LC1 regulates the addition and removal of AMPA-type glutamate receptors at excitatory synapses, which forms one of the mechanisms of synaptic plasticity 37 . By forming immobile complexes, the LC1 traps AMPA receptors and limits intracellular vesicular trafficking within the dendritic shaft.…”

Recent Findings on AMPA Receptor Recycling

“…GRIP1 has been found to present the ability to bind simultaneously both AMPA-Rs and N-Cadherin and associating them with the KIF5 motor protein, thus promoting their contemporaneous dendritic delivery, which would provide synapses instantly with a more complete machinery for establishment and maturation (Heisler et al, 2014 ). Other work has elucidated the already described (Seog, 2004 ) unusual interaction between GRIP1 and the MAP1B light chain in regulating AMPA-R trafficking under basal conditions (Palenzuela et al, 2017 ). MAP1B decorates microtubules along the dendrites (Halpain and Dehmelt, 2006 ) and is directly involved in dendritic spines morphogenesis (Tortosa et al, 2011 ).…”

“…This mechanism describes an unusual role for GRIP1in reducing synaptic delivery of AMPA-Rs. However, further investigation is needed, especially because a MAP1B mutant lacking the microtubule binding domain was shown to retain the ability to impair AMPA-mediated currents, arguing against the binding of MAP1B to microtubules as the trapping mechanism for GRIP1-GluA2 complexes (Palenzuela et al, 2017 ).…”