Research highlights

Neurodegenerative disorders: Pathways to treatment

Nature Reviews Neuroscience 8, 166 (March 2007) | doi:10.1038/nrn2107

The motor deficits observed in Parkinson's disease (PD) result from abnormalities in basal ganglia activity. An imbalance between the activity of striatal projection neurons targeting the substantia nigra pars reticulata (direct pathway) and those targeting the lateral globus pallidus (indirect pathway) is thought to be important in causing these deficits. A new study by Kreitzer and Malenka adds to our understanding of the molecular and electrophysiological differences between these pathways.

The researchers used transgenic mice strains that expressed green fluorescent protein (GFP) in medium spiny neurons (MSNs) of either the direct or indirect pathway to visualize these cells in brain slices. Whole-cell voltage-clamp recordings revealed that synapses onto indirect pathway MSNs have a higher neurotransmitter release probability and a higher density of NMDA (N-methyl-D-aspartate) receptors than those onto direct-pathway MSNs. Indirect pathway MSNs have increased excitability in response to depolarizing currents.

These properties indicated that synaptic plasticity might be greater at indirect pathway synapses. Indeed, long-term depression (LTD) could be induced at indirect pathway synapses, but not at direct pathway synapses. LTD was blocked by a cannabinoid CB1 receptor antagonist, showing that endocannabinoids released by MSNs are crucial. Presynaptic terminals at both direct and indirect pathway synapses express CB1 receptors, indicating that the two pathways probably differ in terms of the synthesis or release of endocannabinoids.

LTD was also shown to require dopamine receptor activation. To determine whether depletion of dopamine in PD might cause motor deficits partially by preventing LTD induction, the researchers used two mouse models of PD. LTD could not be induced at indirect pathway synapses in these models. However, LTD could be rescued by quinpirole, a dopamine D2 receptor agonist, or URB597, an inhibitor of fatty acid amide hydrolase, which degrades endocannabinoids. URB597, in combination with quinpirole, also alleviated the motor deficits observed in these models. This indicates that stimulating LTD induction by boosting dopamine and endocannabinoid levels might help to improve the motor symptoms of PD.

This study increases our knowledge of the properties of the direct and indirect striatal projection pathways and how they might be disrupted by dopamine depletion. Enhancing endocannabinoid as well as dopamine levels at indirect pathway synapses might be a valid therapeutic target for PD.

Author: Katherine Whalley