title: ANKS1B Gene Product AIDA-1 Controls Hippocampal Synaptic Transmission by Regulating GluN2B Subunit Localization.
abstract: NMDA receptors (NMDARs) are key mediators of glutamatergic transmission and synaptic plasticity, and their dysregulation has been linked to diverse neuropsychiatric and neurodegenerative disorders. While normal NMDAR function requires regulated expression and trafficking of its different subunits, the molecular mechanisms underlying these processes are not fully understood. Here we report that the amyloid precursor protein intracellular domain associated-1 protein (AIDA-1), which associates with NMDARs and is encoded by ANKS1B, a gene recently linked to schizophrenia, regulates synaptic NMDAR subunit composition. Forebrain-specific AIDA-1 conditional knock-out (cKO) mice exhibit reduced GluN2B-mediated and increased GluN2A-mediated synaptic transmission, and biochemical analyses show AIDA-1 cKO mice have low GluN2B and high GluN2A protein levels at isolated hippocampal synaptic junctions compared with controls. These results are corroborated by immunocytochemical and electrophysiological analyses in primary neuronal cultures following acute lentiviral shRNA-mediated knockdown of AIDA-1. Moreover, hippocampal NMDAR-dependent but not metabotropic glutamate receptor-dependent plasticity is impaired in AIDA-1 cKO mice, further supporting a role for AIDA-1 in synaptic NMDAR function. We also demonstrate that AIDA-1 preferentially associates with GluN2B and with the adaptor protein Ca(2+)/calmodulin-dependent serine protein kinase and kinesin KIF17, which regulate the transport of GluN2B-containing NMDARs from the endoplasmic reticulum (ER) to synapses. Consistent with this function, GluN2B accumulates in ER-enriched fractions in AIDA-1 cKO mice. These findings suggest that AIDA-1 regulates NMDAR subunit composition at synapses by facilitating transport of GluN2B from the ER to synapses, which is critical for NMDAR plasticity. Our work provides an explanation for how AIDA-1 dysfunction might contribute to neuropsychiatric conditions, such as schizophrenia.
authors.affiliation: Dominick P. Purpura Department of Neuroscience.
authors.forename: Jaafar O
authors.initials: JO
authors.lastname: Tindi
authors.affiliation: Dominick P. Purpura Department of Neuroscience.
authors.forename: Andrés E
authors.identifier: http://orcid.org/0000-0001-8795-9238
authors.initials: AE
authors.lastname: Chávez
authors.affiliation: Dominick P. Purpura Department of Neuroscience.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Cvejic
authors.affiliation: Dominick P. Purpura Department of Neuroscience.
authors.forename: Erika
authors.identifier: http://orcid.org/0000-0002-4363-3962
authors.initials: E
authors.lastname: Calvo-Ochoa
authors.affiliation: Dominick P. Purpura Department of Neuroscience.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Castillo
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York 10461 bryen.jordan@einstein.yu.edu.
authors.forename: Bryen A
authors.initials: BA
authors.lastname: Jordan
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000737:chemistry / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits / Q000032:analysis / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis / Q000502:physiology*; D013569:Synapses / Q000737:chemistry / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: C489945:ANKS1B protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C121001:NR2B NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate
keywords: CASK; KIF17; NMDAR; endoplasmic reticulum; plasticity; trafficking