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 N-methyl-D-aspartate receptor (NMDAR) multiprotein complexes and functionally interacts with the NR2A subunits and the extracellular signal-regulated kinases 1 and 2 (ERK) 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 knockouts 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.

IQGAPs as Key Regulators of Actin-cytoskeleton Dynamics

“…In dissociated hippocampal neurons, IQGAPs accumulate at actin-rich cellular structures such as axon growth cones and spines Swiech et al, 2011). Consistently, IQGAPs are required for axon outgrowth and spine morphology (Gao et al, 2011). Although the above regulatory mechanisms that are performed by IQGAP1 in actin dynamics can be appli- (Le Clainche et al, 2007).…”

IQGAP1 and its binding proteins control diverse biological functions

“…IQGAP1 also influences the number of dendritic spines (80). Reduction of IQGAP1 in hippocampal neurons with shRNA decreases spine density, and hippocampal neurons from IQGAP1 −/− mice have significantly fewer spines than neurons from wild-type animals.…”

“…Reduction of IQGAP1 in hippocampal neurons with shRNA decreases spine density, and hippocampal neurons from IQGAP1 −/− mice have significantly fewer spines than neurons from wild-type animals. Both synaptic plasticity and memory after fear conditioning are also impaired in the IQGAP1-null mice, while motivational and emotional behaviours remain intact (80). The mechanisms responsible for these changes remain to be characterised in detail, but initial findings implicate IQGAP1 in the regulation of N -methyl-D-aspartate receptor (NMDAR) trafficking and activation.…”

Molecular and behavioral changes associated with adult hippocampus-specific SynGAP1 knockout

“…This biochemical event is shown to critically determine glutamate receptor surface expression and regulate spine dynamics (Gao et al 2011). Collectively, it is conceivable that the SynGAP1-mediated signaling pathway essential for glutamatergic synapse formation during development may play a similar role in adulthood by controlling synapse number and morphology, as well as adaptive synaptic changes involving synaptic glutamate receptor insertion.…”