Mouse study targets GluN2B receptor subunit in movement-control neurons
Written by Marisa Wexler, MS | June 8, 2026
- Many people with Parkinson’s disease develop dyskinesia, or uncontrolled movements, after long-term levodopa treatment.
- In a mouse model, dyskinesia was linked to abnormal levels of the GluN2B receptor subunit in specific movement-control neurons.
- An experimental gene therapy strategy that reduced GluN2B levels in mice prevented and eased dyskinesia without reducing levodopa’s benefits.
Levodopa, a standard treatment for Parkinson’s disease, can cause uncontrolled movements called dyskinesia — and this side effect may be driven by changes in a specific receptor component in certain brain cells, a new study shows.
Scientists found that an experimental gene therapy strategy aimed at decreasing levels of this receptor component in those specific brain cells could blunt dyskinesia’s development and substantially ease established dyskinesia in a mouse model.
“This is a way that we might be able to control dyskinesia with a completely novel strategy,” D. James Surmeier, PhD, senior author of the study at Northwestern University, said in a university news story. “Nearly 80 percent of Parkinson’s disease patients will develop dyskinesia. At present, we have a very limited set of tools to help these patients right now. This work points to the possibility of a non-invasive gene therapy that would be transformative.”
The study, “Cell- and state-specific plasticity of striatal glutamatergic synapses is critical to the expression of levodopa-induced dyskinesia,” was published in Neuron.
Levodopa treatment can trigger dyskinesia
Parkinson’s is a neurological disorder marked by the degeneration and death of brain cells that make dopamine, a signaling molecule that’s key for coordinating movements. Low dopamine levels ultimately drive Parkinson’s symptoms.
Levodopa and its derivatives primarily work by being converted into dopamine in the brain. These medications have for decades been a gold standard of Parkinson’s treatment, and they can be highly effective for easing disease symptoms — but as with any medical treatment, levodopa can cause side effects. In particular, many people who take levodopa long term develop dyskinesia, defined by jerky, uncontrollable movements.
Although it’s well-established that levodopa can trigger dyskinesia, the precise molecular mechanisms by which this drug causes this side effect have been obscure.
Working in a mouse model, researchers found that repeated levodopa treatment that induced dyskinesia led to molecular abnormalities in a subset of brain cells called indirect pathway spiny projection neurons, or iSPNs. Under normal circumstances, these nerve cells are thought to help the brain prevent unwanted movements.
The researchers specifically found that dyskinesia was linked to increased levels of N-methyl-D-aspartate (NMDA) receptors containing a specific subunit called GluN2B in iSPNs. NMDA receptors normally help nerve cells communicate with each other, but changes in these receptors can disrupt nerve-to-nerve communication.
“Connections between neurons dictate when they become active and how they perform their duties in controlling movement. In late-stage [Parkinson’s] patients, levodopa begins to ‘scramble’ these connections, which we think leads to uncontrolled movement or dyskinesia,” Surmeier said. “When we induce dyskinesia, we see this change in NMDA receptors in this subset of striatal neurons thought to be responsible for suppression of unwanted movement.”
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