Researchers at Vanderbilt University have discovered a new “push-pull” mechanism in the brain that one day could lead to new treatments for movement disorders such as Parkinson’s disease, as well as stress-related disorders and addiction.
In this week’s Nature Neuroscience, the researchers describe a “functional interaction” between two proteins involved in transmitting signals across the synapse, or gap, between certain nerve cells in mice. The novel interaction was found in the striatum, the brain region that regulates movement and motor coordination.
One of the proteins, CaM kinase II, is widely known to activate synaptic transmission in many regions of the brain. The other protein, DGL-alpha, makes an “endocannabinoid” called 2-AG that depresses synaptic transmission. Endocannabinoids are the natural lipid signaling molecules that are mimicked by the active ingredients of marijuana.
The study found that CaM kinase II normally inhibits DGL-alpha, thereby exerting a tonic brake on the production of 2-AG. Disruption of CaM kinase II signaling in a mouse model increased 2-AG production, resulting in enhanced synaptic depression and the inhibition of normal activity and movement in the mice.
This suggests that a disruption in the balance between the two proteins may play a role in movement disorders such as Parkinson’s disease, said the paper’s corresponding author, Roger Colbran, Ph.D. However, “there are not yet any studies showing that this mechanism is important in a human population,” said Colbran, professor of Molecular Physiology and Biophysics.
Since these proteins are widely distributed throughout the brain, further research could lead to “novel strategies to fine-tune synaptic transmission … in multiple neurological and psychiatric disorders,” the researchers concluded.
Colbran’s collaborators in this study included Sachin Patel, M.D., Ph.D., assistant professor of Psychiatry, who is studying the protein interaction for its potential role in stress disorders, and Danny Winder, Ph.D., professor of Molecular Physiology and Biophysics, who is interested in its possible impact on addiction and relapse.
The experimental work was spearheaded by the first author, Brian Shonesy, Ph.D., visiting research fellow in Molecular Physiology and Biophysics.
Colbran said the research could not have been done without the help of Vanderbilt’s “outstanding” research facilities, including the Proteomics Laboratory, the small molecule Mass Spectrometry Core, and the Murine Neurobehavioral Laboratory.
“That’s why I’m here,” said the British-born Colbran, who joined the Vanderbilt faculty in 1986. “That’s what makes science fun, when you can do it in first-rate facilities and with great colleagues.”
The Vanderbilt researchers were supported in part by National Institutes of Health grants MH063232, MH090412, MH065215, NS078291, NS007491, NS073700 and AA019455.
