Summary: A new study shows that when one synapse strengthens, nearby synapses weaken, and this coordination is driven by the protein Arc.
Source: MIT
Neural circuits adapt through synaptic plasticity: neurons form stronger or new connections to encode experience. New research from the Picower Institute for Learning and Memory at MIT reveals a simple, local rule that preserves balance during this process. When an individual synapse strengthens, nearby synapses within roughly 50 micrometers weaken, a change orchestrated by the activity of the protein Arc.
Mriganka Sur, senior author and Paul E. and Lilah Newton Professor of Neuroscience at MIT, describes the finding as a fundamental rule underlying complex brain dynamics. He compares it to the collective movement of a school of fish: many cells can change behavior reliably if each follows a straightforward local rule. In this case, the rule ensures neurons do not become overstimulated as some synapses potentiate.
“When a synapse increases its strength, nearby synapses decrease their strength through a defined molecular mechanism,” Sur says. This locally coordinated potentiation and depression provides a mechanistic explanation for how neurons achieve stable plasticity while remaining flexible.
Multiple experimental approaches
Lead authors Sami El-Boustani and Jacque Pak Kan Ip used a combination of advanced techniques to activate and track synaptic plasticity in the visual cortex of awake mice. In one key experiment they altered a neuron’s receptive field—the specific region of visual space that drives that neuron—by selectively strengthening a single spine on a dendrite. Neuronal input arrives at tiny protrusions called spines, and the researchers identified the exact spine associated with the receptive field change.
To induce targeted plasticity, they paired presentation of a visual target at a new location with brief pulses of blue light delivered to the visual cortex. The neurons were engineered to respond to light (optogenetics), so the light pulses reinforced the neuron’s responses to the new visual position. Repeating this pairing caused the targeted synapse to grow and strengthen, effectively encoding the shifted receptive field.
Under two-photon microscopy, the team observed that as the targeted spine enlarged, neighboring spines on the same dendrite shrank. Control neurons that did not receive the optogenetic stimulation showed no comparable structural changes. To validate these observations at higher resolution, the researchers dissected the manipulated tissue and used three-dimensional electron microscopy. That analysis confirmed the local structural remodeling previously seen in vivo—representing one of the longest dendritic reconstructions performed after live imaging.
The investigators also tested a classical sensory-plasticity paradigm: monocular deprivation. Temporarily closing one eye causes synapses associated with the deprived eye to weaken while synapses tied to the open eye strengthen. When the deprived eye was reopened, synapses rearranged again, and again the team found that strengthening synapses were accompanied by nearby weakening, consistent with the locally coordinated rule.
Arc and AMPA receptors mediate local balance
To understand the molecular basis of the coordinated changes, the researchers tracked AMPA-type glutamate receptors, which mediate fast excitatory transmission and are a key determinant of synaptic strength. Growing, potentiated spines showed increased AMPA receptor expression, while shrinking, weakened neighbors showed reduced AMPA receptor levels.
The immediate early gene product Arc regulates AMPA receptor trafficking, so the team monitored Arc in living animals using a specialized chemical tag developed in collaboration with partners in Japan. Visualization of Arc revealed that synapses surrounding a potentiated spine showed enriched Arc expression. Spines with elevated Arc reduced AMPA receptor expression, while spines with less Arc were free to recruit more AMPA receptors.
“Arc appears to maintain a local balance of synaptic resources,” says Ip. “If one synapse increases its strength, Arc helps ensure neighboring synapses decrease to preserve overall stability.” The finding clarifies a longstanding puzzle: previous studies had noted Arc upregulation during plasticity despite Arc’s role in weakening synapses. These results show that increased Arc at nearby spines is part of a compensatory mechanism that permits focal strengthening without destabilizing the neuron.
Sur notes that this local rule helps explain how learning and memory processes can operate at the level of individual neurons: Hebbian strengthening of activated synapses, coupled with heterosynaptic weakening of nearby connections, cooperatively reshapes a neuron’s functional responses.
Funding: The work was supported by the Picower Institute Innovation Fund, The Simons Center for the Social Brain, a Marie Curie postdoctoral fellowship, a Human Frontier Science Program Long-Term Fellowship, the National Institutes of Health (grants NS090473, EY007023), the National Science Foundation (EF1451125) and KAKENHI (15H04258, 15H02358, 17H06312).
Source: David Orenstein, MIT. Publisher: NeuroscienceNews.com. Image credit: Sur et al. Original research: “Locally coordinated synaptic plasticity of visual cortex neurons in vivo,” Science, published June 22, 2018. doi:10.1126/science.aao0862
Abstract
Locally coordinated synaptic plasticity of visual cortex neurons in vivo
Plasticity of cortical responses in vivo involves activity-dependent changes at synapses, but how different forms of synaptic plasticity combine to produce functional changes in neurons has been unclear. The authors show that spike timing–induced receptive field plasticity in mouse visual cortex is anchored by increased synaptic strength at specific identified spines, accompanied by a slower decrease in the strength of adjacent spines. This local coordination of potentiation and depression involves redistribution of AMPA receptors mediated by targeted expression of the immediate early gene product Arc. Hebbian potentiation of activated synapses and heterosynaptic weakening of neighbors together drive cell-wide plasticity of neuronal responses.