Editors' ChoiceNeuroscience

Sorting out memory and learning

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Sci. Signal.  02 May 2017:
Vol. 10, Issue 477, eaan5454
DOI: 10.1126/scisignal.aan5454

Mutations in AMPA receptor recycling machinery underlie cognitive impairment in an intellectual disorder and in neurodegenerative diseases.

Learning and adapting to one’s environment depends on experience-dependent modification of synaptic function and neuronal connectivity in the brain. Synaptic strength is adjusted through the dynamic endocytosis, sorting and recycling or degradation of AMPA receptors (AMPARs). Long-term potentiation (LTP) is a measure of synaptic plasticity, specifically strengthening, that underlies learning and memory. Two studies show that mutations in endocytic trafficking machinery cause cognitive impairment by missorting of AMPARs, resulting in the trapping of AMPARs intracellularly.

Chiu et al. found that the neuron-specific endocytic recycling protein GRASP1 is critical to cognition. They identified two point mutations in GRASP1 in some patients with X-linked intellectual disability (ID) disorder. Neurons in mice lacking Grasp1 or expressing the ID-associated point mutations in Grasp1 failed to traffic AMPARs to the synapse during experience-induced LTP and had altered spine development. GRASP1-defective mice performed worse than wild-type mice on associative and spatial learning and memory tasks. Expression of wild-type but not ID-mutant GRASP1 rescued spine morphology and learning and memory function in Grasp1 knockout mice.

In another study, Temkin et al. found that the multiprotein endosomal sorting complex called the retromer is critical for LTP-induced delivery of AMPARs to the synapse. Lentiviral-mediated knockdown of the critical retromer component VPS35 in the hippocampi of mature mice impaired LTP and decreased synaptic AMPAR abundance in hippocampal neurons. Point mutations in VPS35 are associated with Alzheimer’s and Parkinson’s diseases. Curiously, LTP in cultured VPS35-deficient neurons was rescued by expression of an Alzheimer’s disease-associated mutation (which has been found in a single patient thus far), but not by that of the Parkinson’s disease-associated mutation (which is high-penetrance and familial). Nonetheless, together these findings provide in vivo insight into how AMPAR trafficking contributes to the pathophysiology of common cognitive disorders.

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