Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1

Ameet S Sengar; Hongbin Li; Wenbo Zhang; Celeste Leung; Arun K Ramani; Ner Mu Saw; Yongqian Wang; YuShan Tu; P Joel Ross; Stephen W Scherer; James Ellis; Michael Brudno; Zhengping Jia; Michael W Salter

doi:10.1016/j.celrep.2019.11.087

Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1

Cell Rep. 2019 Dec 24;29(13):4285-4294.e5. doi: 10.1016/j.celrep.2019.11.087.

Authors

Affiliations

¹ Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
² Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
³ Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁴ Biology Department, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada.
⁵ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada.
⁶ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁷ Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada.
⁸ Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: michael.salter@sickkids.ca.

PMID: 31875540
DOI: 10.1016/j.celrep.2019.11.087

Abstract

NMDA receptors (NMDARs) are critical for physiological synaptic plasticity, learning, and memory and for pathological plasticity and neuronal death. The GluN1 subunit is encoded by a single gene, GRIN1, with 8 splice variants, but whether the diversity generated by this splicing has physiological consequences remains enigmatic. Here, we generate mice lacking from the GluN1 exon 5-encoded N1 cassette (GluN1a mice) or compulsorily expressing this exon (GluN1b mice). Despite no differences in basal synaptic transmission, long-term potentiation in the hippocampus is significantly enhanced in GluN1a mice compared with that in GluN1b mice. Furthermore, GluN1a mice learn more quickly and have significantly better spatial memory performance than do GluN1b mice. In addition, in human iPSC-derived neurons in autism spectrum disorder NMDARs show characteristics of N1-lacking GluN1. Our findings indicate that alternative splicing of GluN1 is a mechanism for controlling physiological long-lasting synaptic potentiation, learning, and memory.

Keywords: GluN1; N1 cassette; NMDA Receptor; autism; long-term potentiation; splicing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alternative Splicing*
Animals
Autism Spectrum Disorder / genetics*
Autism Spectrum Disorder / metabolism
Autism Spectrum Disorder / pathology
Cell Death / genetics
Cell Differentiation
Excitatory Postsynaptic Potentials / physiology
Exons
Hippocampus / metabolism
Hippocampus / pathology
Humans
Induced Pluripotent Stem Cells / metabolism
Induced Pluripotent Stem Cells / pathology
Long-Term Potentiation / genetics*
Mice
Mice, Knockout
Nerve Tissue Proteins / deficiency
Nerve Tissue Proteins / genetics*
Neurons / metabolism*
Neurons / pathology
Primary Cell Culture
Protein Subunits / deficiency
Protein Subunits / genetics
Receptors, N-Methyl-D-Aspartate / deficiency
Receptors, N-Methyl-D-Aspartate / genetics*
Spatial Memory / physiology
Synapses / metabolism
Synaptic Transmission

Substances

GRIN1 protein, human
Gprin1 protein, mouse
Nerve Tissue Proteins
Protein Subunits
Receptors, N-Methyl-D-Aspartate
N-methyl D-aspartate receptor subtype 2A