USC Dornsife researchers develop tool to break brain circuits with molecular precision

Scientists have developed a powerful new method for selectively and reversibly breaking connections between brain cells — a leap forward that could transform how we study the brain processes and, one day, how we treat neurological disorders such as epilepsy, addiction and post-traumatic stress disorder.

The study, led by USC Dornsife College of Letters, Arts and Sciences neurobiologist Don Arnold and published in eLife, introduces a suite of genetically engineered tools that allow researchers to eliminate either excitatory or inhibitory synapses — the specialized junctions where neurons communicate — with molecular precision. Crucially, the technique affects only the targeted synapses, leaving the rest of the neuron intact.

This level of specificity, Arnold says, marks a first in neuroscience. “As far as I know, no one else has ever been able to ablate [knock out] specific synapses without affecting the whole neuron,” he said.

The ability to selectively dismantle parts of a neural network — and then allow them to regrow — opens new paths to understanding how microcircuits in the brain govern perception, behavior and memory.

Arnold, professor of biological sciences and biomedical engineering, and his team created two molecular tools — one that targets excitatory synapses and another that targets inhibitory ones — using an approach inspired by the brain’s own system for recycling proteins. The technique involves E3 ligases, enzymes that normally help dispose of damaged proteins by tagging them with a molecule called ubiquitin. Once tagged, the proteins are sent to the proteasome — a cellular structure Arnold likens to a “miniature wood-chipper” — to be broken down and repurposed. 

In this study, the researchers paired the E3 ligases with antibody-like proteins that bind to specific synaptic scaffolding proteins. The result: a custom-built tool that directs the brain’s trash-disposal system to eliminate key components of either excitatory or inhibitory synapses — even though they’re healthy. Without their molecular scaffolding, the synapses fall apart and the neuron cannot transmit the signal to the next neuron, disrupting the circuit.

Arnold named the tools PFE3 and GFE3, which target excitatory and inhibitory synapses respectively. He also developed two versions of GFE3 that can be activated on demand: one by light (paGFE3) and one by a chemical signal (chGFE3). 

Significantly, the effects are reversible. When expression of the tools is turned off, neurons regrow their lost synapses within days. That feature gives researchers the power not just to remove a connection and observe the result — but to restore it and observe the recovery. 

“This reversibility and the ability to target synapses so specifically make this method uniquely powerful for studying brain circuits,” Arnold said.

While potential therapeutic use is still far off, the technology could eventually guide the development of treatments that target malfunctioning brain circuits with unprecedented precision, leaving healthy ones untouched.