Memories in the Making

Researchers provide new insight into how the brain makes memories.

Every time you make a memory, somewhere in your brain a tiny filament reaches out from one neuron and forms an electrochemical connection to a neighboring neuron.

A team of biologists at Vanderbilt University, headed by Associate Professor of Biological Sciences Donna Webb, studies how these connections are formed at the molecular and cellular level.

The filaments that make these new connections are called dendritic spines and, in a series of experiments described in the April 17 issue of the Journal of Biological Chemistry, the researchers report that a specific signaling protein, Asef2, a member of a family of proteins that regulate cell migration and adhesion, plays a critical role in spine formation. This is significant because Asef2 has been linked to autism and the co-occurrence of alcohol dependency and depression.

“Alterations in dendritic spines are associated with many neurological and developmental disorders, such as autism, Alzheimer’s disease and Down Syndrome,” said Webb. “However, the formation and maintenance of spines is a very complex process that we are just beginning to understand.”

Neuron cell bodies produce two kinds of long fibers that weave through the brain: dendrites and axons. Axons transmit electrochemical signals from the cell body of one neuron to the dendrites of another neuron. Dendrites receive the incoming signals and carry them to the cell body. This is the way that neurons communicate with each other.

As they wait for incoming signals, dendrites continually produce tiny flexible filaments called filopodia. These poke out from the surface of the dendrite and wave about in the region between the cells searching for axons. At the same time, biologists think that the axons secrete chemicals of an unknown nature that attract the filopodia.

When one of the dendritic filaments makes contact with one of the axons, it begins to adhere and to develop into a spine. The axon and spine form the two halves of a synaptic junction. New connections like this form the basis for memory formation and storage.

Autism has been associated with immature spines, which do not connect properly with axons to form new synaptic junctions. However, a reduction in spines is characteristic of the early stages of Alzheimer’s disease. This may help explain why individuals with Alzheimer’s have trouble forming new memories.

This image shows filapodia extending out from dendrite.

This is a fluorescent microphotograph of neurons that shows filapodia extending out from dendrite. Image credit: Webb Lab / Vanderbilt.

The formation of spines is driven by actin, a protein that produces microfilaments and is part of the cytoskeleton. Webb and her colleagues showed that Asef2 promotes spine and synapse formation by activating another protein called Rac, which is known to regulate actin activity. They also discovered that yet another protein, spinophilin, recruits Asef2 and guides it to specific spines.

“Once we figure out the mechanisms involved, then we may be able to find drugs that can restore spine formation in people who have lost it, which could give them back their ability to remember,” said Webb.

About this memory research

Co-authors of the study are graduate students J. Corey Evans and Cristina Robinson and postdoctoral scholar Mingjian Shi from the Department of Biological Sciences and the Kennedy Center for Research on Human Development.

Funding: The research was supported by National Institutes of Health grants GM092914, GM008554, MH071674 and National Center for Research Resources grant S10RR025524.

Source: David Salisbury – Vanderbilt
Image Credit: The image is credited to Webb Lab / Vanderbilt
Original Research: Abstract for “The Guanine Nucleotide Exchange Factor (GEF) Asef2 Promotes Dendritic Spine Formation via Rac Activation and Spinophilin-dependent Targeting” by J. Corey Evans, Cristina M. Robinson, Mingjian Shi, and Donna J. Webb in Journal of Biological Chemistry. Published online March 6 2015 doi:10.1074/jbc.M114.605543


Abstract

The Guanine Nucleotide Exchange Factor (GEF) Asef2 Promotes Dendritic Spine Formation via Rac Activation and Spinophilin-dependent Targeting

Dendritic spines are actin-rich protrusions that establish excitatory synaptic contacts with surrounding neurons. Reorganization of the actin cytoskeleton is critical for the development and plasticity of dendritic spines, which is the basis for learning and memory. Rho family GTPases are emerging as important modulators of spines and synapses, predominantly through their ability to regulate actin dynamics. Much less is known, however, about the function of guanine nucleotide exchange factors (GEFs), which activate these GTPases, in spine and synapse development. In this study we show that the Rho family GEF Asef2 is found at synaptic sites, where it promotes dendritic spine and synapse formation. Knockdown of endogenous Asef2 with shRNAs impairs spine and synapse formation, whereas exogenous expression of Asef2 causes an increase in spine and synapse density. This effect of Asef2 on spines and synapses is abrogated by expression of GEF activity-deficient Asef2 mutants or by knockdown of Rac, suggesting that Asef2-Rac signaling mediates spine development. Because Asef2 interacts with the F-actin-binding protein spinophilin, which localizes to spines, we investigated the role of spinophilin in Asef2-promoted spine formation. Spinophilin recruits Asef2 to spines, and knockdown of spinophilin hinders spine and synapse formation in Asef2-expressing neurons. Furthermore, inhibition of N-methyl-D-aspartate receptor (NMDA) activity blocks spinophilin-mediated localization of Asef2 to spines. These results collectively point to spinophilin-Asef2-Rac signaling as a novel mechanism for the development of dendritic spines and synapses.

“The Guanine Nucleotide Exchange Factor (GEF) Asef2 Promotes Dendritic Spine Formation via Rac Activation and Spinophilin-dependent Targeting” by J. Corey Evans, Cristina M. Robinson, Mingjian Shi, and Donna J. Webb in Journal of Biological Chemistry. Published online March 6 2015 doi:10.1074/jbc.M114.605543

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