Progress in Neuroscience Seminars (PINS): Regulation of Neurotransmitter Receptors in the Brain in Health and Disease

Richard L. Huganir, Bloomberg Distinguished Professor, Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD USA Neurotransmitter receptors mediate signal transduction at synaptic connections between neurons in the brain. My laboratory has been elucidating the molecular mechanisms underlying the regulation of glutamate receptors, the major excitatory neurotransmitters receptors in the central nervous system. We have focused on AMPA-type glutamate receptors and have found that they are extensively posttranslationally modified by phosphorylation, palmitoylation and ubiquination. We have shown that these posttranslational modifications of the receptor regulates its ion channel properties and membrane trafficking and are critical for several forms of synaptic plasticity and for learning and memory. We have also identified a variety of AMPA receptor interacting proteins, including GRIP1/2, PICK1, GRASP1, SNX27, KIBRA, and SynGAP, that interact with AMPA receptors and are necessary for their proper subcellular trafficking. This AMPA receptor complex is important for several forms of synaptic plasticity and learning and memory. These studies indicate that the modulation of receptor function is a major mechanism for the regulation of synaptic transmission and is a critical determinant of animal behavior. Recent evidence has indicated that AMPA receptor function may be disrupted in several neurological and psychiatric disorders. Specifically, mutations in SynGAP, GRIP1 and GRASP1 have been found to be associated with cognitive disorders including intellectual disability, autism, and schizophrenia. Diering, G.H., Huganir, R.L. (2018) The AMPA Receptor Code of Synaptic Plasticity. Neuron. 100 (2): 314-329. Roth, R., Cudmore, R., Tan, H., Hong, I., Zhang, Y., Huganir, R. (2019) Cortical Synaptic AMPA Receptor Plasticity During Motor Learning. Neuron. 105 (5):895-908. Gamache, T.R., Araki, Y., Huganir, R.L. (2020) Twenty Years of SynGAP Research: From Synapses to Cognition. J Neurosci. 2020 Feb 19:40 (8):1596-1605.