IQGAP1 Regulates NR2A Signaling, Spine Density, and Cognitive Processes
- 8 June 2011
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 31 (23), 8533-8542
- https://doi.org/10.1523/jneurosci.1300-11.2011
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.This publication has 72 references indexed in Scilit:
- Hippocampal NMDA receptor subunits differentially regulate fear memory formation and neuronal signal propagationHippocampus, 2010
- Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophreniaJournal of Affective Disorders, 2010
- Altered Cortical CDC42 Signaling Pathways in Schizophrenia: Implications for Dendritic Spine DeficitsBiological Psychiatry, 2010
- The synaptic pathology of α-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementiaActa Neuropathologica, 2010
- DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in StrokeCell, 2010
- Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disordersMolecular Psychiatry, 2010
- Regionally Specific Regulation of ERK MAP Kinase in a Model of Antidepressant-Sensitive Chronic DepressionBiological Psychiatry, 2008
- Chemical and morphological alterations of spines within the hippocampus and entorhinal cortex precede the onset of Alzheimer's disease pathology in double knock-in miceJournal of Comparative Neurology, 2007
- The NMDAR subunit NR3A interacts with microtubule-associated protein 1S in the brainBiochemical and Biophysical Research Communications, 2007
- N-Cadherin Regulates Cytoskeletally Associated IQGAP1/ERK Signaling and Memory FormationNeuron, 2007