Neuroscience researchers have revealed how an internal structural component within neurons executes coordinated movements as synaptic connections are strengthened. By separating the remodeling process into two distinct steps during long-term potentiation (LTP), the team shed light on how the internal “skeletons” of dendritic spines change during synaptic plasticity. These insights have implications for understanding a range of neurological, cognitive and neurodegenerative conditions.
Scientists glimpse the “dance” of neuronal skeletons
New findings illuminate mechanisms relevant to developmental conditions such as Williams syndrome
Investigators at Emory University School of Medicine traced how actin-based structures inside neurons coordinate two sequential actions when synapses strengthen. Their findings, published in Nature Neuroscience, reveal how dendritic spines—tiny protrusions that receive signals from neighboring neurons—undergo precise structural changes that accompany enhanced synaptic signaling.
Long-term potentiation, a well-established cellular model of learning and memory, involves both the enlargement of dendritic spines and an increased density of neurotransmitter receptors on the spine surface. In cultured neurons, the researchers could clearly separate two phases of this process: an early step that permits receptor insertion at the surface, and a later step that stabilizes and enlarges the spine.
To follow receptor dynamics, the team engineered a version of a neurotransmitter receptor that becomes fluorescent only when inserted into the cell surface. This allowed direct live imaging of receptor delivery from internal stores to the spine membrane. At the same time, the investigators manipulated the actin cytoskeleton—the filamentous scaffold that gives spines their shape—using pharmacological agents that either loosen or freeze actin dynamics.
Focusing on the ADF/cofilin family of proteins, which sever actin filaments, the group found that controlled severing is a necessary early event. “You need to cut actin filaments to make room for receptors stored inside the cell to be added to the spine surface,” explains senior author James Zheng, PhD, professor of cell biology and neurology. After receptors are inserted, cofilin activity must be reduced so the spine can be stabilized and enlarged.
These two coordinated activities—actin filament severing to enable receptor trafficking, followed by actin stabilization to consolidate spine growth—appear essential for effective synaptic strengthening. Disrupting the balance between these activities alters how receptors move and how spines remodel, which could selectively affect certain cognitive functions.
The work offers a mechanistic clue to some features of Williams syndrome, a rare developmental disorder caused by a deletion of multiple genes on a chromosome. One of the genes in the deleted region encodes LIM kinase 1 (LIMK1), an enzyme that inactivates ADF/cofilin. Loss of LIMK1 could therefore shift the balance of actin remodeling in neurons, altering the dynamics of spine remodeling and contributing to the syndrome’s characteristic profile of cognitive strengths and weaknesses—impaired spatial perception and social judgment, alongside relative preservation of language and musical abilities.
“Cytoskeletal remodeling must be tightly regulated: it is required for certain aspects of long-term potentiation but must also be held in check,” Zheng says. “Changes in LIM kinase or ADF/cofilin activity could influence some neural processes while leaving others intact.” He also notes that actin regulation by ADF/cofilin is likely a convergent target in numerous neurological disorders where synaptic structure and function are disrupted.
There are practical implications for drug development. Pharmaceutical efforts have explored LIM kinase inhibitors for conditions such as glaucoma and cancer. Zheng cautions that altering LIM kinase activity pharmacologically could unintentionally perturb cognitive processes. At the same time, the temporal dynamics revealed by this study suggest there may be controlled windows when modulating actin remodeling could enhance learning or memory formation.
The work was supported by the National Institutes of Health.
Gu et al. ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity. Nature Neuroscience. Advance online publication (2010).
Writer: Quinn Eastman
Contact: Holly Korschun
Source: Emory University
