Palenzuela Rocío, Gutiérrez Yolanda, Draffin Jonathan E, Lario Argentina, Benoist Marion, Esteban José A
Department of Neurobiology, Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Madrid 28049, Spain, and.
School of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid 28223, Spain.
J Neurosci. 2017 Oct 11;37(41):9945-9963. doi: 10.1523/JNEUROSCI.0505-17.2017. Epub 2017 Sep 13.
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型谷氨酸受体（AMPARs）向突触膜的调控转运是决定大脑中兴奋性突触传递强度的关键机制。在这项研究中，我们发现微管相关蛋白MAP1B在调节AMPARs进入突触后膜方面具有新作用。利用雌雄小鼠和大鼠，我们发现MAP1B轻链（LC）在海马神经元的树突-胞体区积累，在那里它在微管上形成固定复合物，限制囊泡运输。这些复合物限制了AMPARs在树突中的移动性，导致受体在细胞内滞留，并损害其到达树突表面和棘的能力。因此，增加MAP1B-LC的表达会抑制AMPAR介导的突触传递。这种效应对AMPAR的GluA2亚基具有特异性，并且需要谷氨酸受体相互作用蛋白1（GRIP1）与MAP1B-LC相互作用。因此，MAP1B-LC代表了GRIP1-AMPARs与微管之间的另一种联系，这种联系不会导致有效的运输，而是限制了用于突触插入的AMPARs的可用性，直接影响突触传递。神经元改变其突触连接的能力，即突触可塑性，被认为是学习和记忆的细胞基础。突触可塑性的一种机制是在兴奋性突触处对AMPA型谷氨酸受体（AMPARs）进行调控性添加和去除。在本研究中，我们发现一种微管相关蛋白，MAP1B轻链（MAP1B-LC）参与了这一过程。MAP1B-LC沿着树突形成固定复合物。这些复合物限制细胞内囊泡运输，并将AMPARs捕获在树突轴内。通过这种方式，MAP1B限制了AMPARs到达树突棘和突触后膜，从而导致突触传递下调。
