Shifting the Balance

Abstract

The striatum controls motor activity through the balance of the activity of a direct and indirect pathway. Kreitzer and Malenka used mice engineered to express green fluorescent protein in neurons of the direct pathway or indirect pathway to show that the cells of the indirect pathway exhibited (i) higher probability of neurotransmitter release, (ii) increased ratios of NMDA- to AMPA-type glutamate receptors, and (iii) increased rate of synaptic activity compared with cells of the direct pathway. High-frequency afferent stimulation only triggered long-term depression (LTD) in the indirect pathway, and application of an antagonist of the endocannabinoid receptor CB1 or the D2 dopamine receptor blocked this response. However, this difference was not caused by a lack of CB1 receptors in the direct pathway, because application of CB1 agonist increased both direct and indirect pathway excitatory postsynaptic potentials. Instead, endocannabinoid release or synthesis in response to synaptic activity appeared to be limited to the indirect pathway. Mouse models of Parkinson's disease showed a lack of an indirect pathway LTD response that was restored if the slices were exposed to a D2 agonist or an inhibitor of endocannabinoid degradation. In the Parkinson's model mice, treatment with both a D2 agonist and the endocannabinoid degradation inhibitor reduced catalepsy and improved motor activity compared to treatment with the D2 agonist alone. A. C. Kreitzer, R. C. Malenka, Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. Nature 445 , 643-647 (2007). [PubMed]