title: IQGAP1 regulates NR2A signaling, spine density, and cognitive processes.
abstract: General or brain-region-specific decreases in spine number or morphology accompany major neuropsychiatric disorders. It is unclear, however, whether changes in spine density are specific for an individual mental process or disorder and, if so, which molecules confer such specificity. Here we identify the scaffolding protein IQGAP1 as a key regulator of dendritic spine number with a specific role in cognitive but not emotional or motivational processes. We show that IQGAP1 is an important component of NMDAR multiprotein complexes and functionally interacts with the NR2A subunits and the extracellular signal-regulated kinase 1 (ERK1) and ERK2 signaling pathway. Mice lacking the IQGAP1 gene exhibited significantly lower levels of surface NR2A and impaired ERK activity compared to their wild-type littermates. Accordingly, primary hippocampal cultures of IQGAP1(-/-) neurons exhibited reduced surface expression of NR2A and disrupted ERK signaling in response to NR2A-dependent NMDAR stimulation. These molecular changes were accompanied by region-specific reductions of dendritic spine density in key brain areas involved in cognition, emotion, and motivation. IQGAP1 knock-outs exhibited marked long-term memory deficits accompanied by impaired hippocampal long-term potentiation (LTP) in a weak cellular learning model; in contrast, LTP was unaffected when induced with stronger stimulation paradigms. Anxiety- and depression-like behavior remained intact. On the basis of these findings, we propose that a dysfunctional IQGAP1 gene contributes to the cognitive deficits in brain disorders characterized by fewer dendritic spines.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, The Asher Center for Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Can
authors.initials: C
authors.lastname: Gao
authors.forename: Shanti F
authors.initials: SF
authors.lastname: Frausto
authors.forename: Anita L
authors.initials: AL
authors.lastname: Guedea
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Tronson
authors.forename: Vladimir
authors.initials: V
authors.lastname: Jovasevic
authors.forename: Katie
authors.initials: K
authors.lastname: Leaderbrand
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Corcoran
authors.forename: Yomayra F
authors.initials: YF
authors.lastname: Guzmán
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Swanson
authors.forename: Jelena
authors.initials: J
authors.lastname: Radulovic
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology; D003213:Conditioning, Psychological / Q000502:physiology; D049229:Dendritic Spines / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D004644:Emotions / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005239:Fear / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000378:metabolism*; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000502:physiology; D057567:Memory, Long-Term / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016622:Silver Staining; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C101203:IQ motif containing GTPase activating protein 1; C120997:NR2A NMDA receptor; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D020703:ras GTPase-Activating Proteins