Abstract
The ability to distinguish between similar experiences is a critical feature of episodic memory and is primarily regulated by the dentate gyrus (DG) region of the hippocampus. However, the molecular mechanisms underlying such pattern separation tasks are poorly understood. We report a novel role for the small GTPase ADP ribosylation factor 4 (Arf4) in controlling pattern separation by regulating dendritic spine development. Arf4+/− mice at 4–5 months of age display severe impairments in a pattern separation task, as well as significant dendritic spine loss and smaller miniature excitatory post-synaptic currents (mEPSCs) in granule cells of the DG. Arf4 knockdown also decreases spine density in primary neurons, whereas Arf4 overexpression promotes spine development. A constitutively active form of Arf4, Arf4-Q71L, promotes spine density to an even greater extent than wildtype Arf4, whereas the inactive Arf4-T31N mutant does not increase spine density relative to controls. Arf4′s effects on spine development are regulated by ASAP1, a GTPase-activating protein that modulates Arf4 GTPase activity. ASAP1 overexpression decreases spine density, and this effect is partially rescued by concomitant overexpression of wildtype Arf4 or Arf4-Q71L. In addition, Arf4 overexpression rescues spine loss in primary neurons from an Alzheimer's disease-related apolipoprotein (apo) E4 mouse model. Our findings suggest that Arf4 is a critical modulator of DG-mediated pattern separation by regulating dendritic spine development.
Highlights
In the adult mammalian brain, the hippocampus plays a central role in the encoding and storage of certain types of memory, including spatial and episodic memory [1,2]
X-gal staining of 4.5-month-old ADP ribosylation factor 4 (Arf4)+/2 mice showed that Arf4 is highly expressed in the dentate gyrus (DG) (Figs. 1C and D), prompting us to investigate the potential roles of Arf4 in DGdependent memory tasks
We show that the small GTPase Arf4 is a novel modulator of DG-dependent pattern separation tasks by regulating dendritic spine development
Summary
In the adult mammalian brain, the hippocampus plays a central role in the encoding and storage of certain types of memory, including spatial and episodic memory [1,2]. The dentate gyrus (DG) subregion of the hippocampus mediates episodic memory formation and the disambiguation of similar but discrete events, a phenomenon known as pattern separation [3,4,5,6]. Spine morphology correlates with synaptic strength and structural plasticity; for instance, thin spines are highly motile and likely to respond to activity-induced changes, whereas mushroom spines have larger post-synaptic densities (PSDs) and are more stable [13,14]. Aberrations in spine density and morphology are associated with a number of neurological disorders, including Alzheimer’s disease (AD) [15,16,17]. Apolipoprotein (apo) E4–a major genetic risk factor for Alzheimer’s disease–decreases spine density both in vivo [18,19]
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