Striatal Cholinergic Interneurons in a Knock-in Mouse Model of L-DOPA-Responsive Dystonia.

Striatal cholinergic dysfunction is a common phenotype associated with various forms of dystonia in which anti-cholinergic drugs have some therapeutic benefits. However, the underlying substrate of striatal cholinergic defects in dystonia remain poorly understood. In this study, we used a recently developed knock-in mouse model of dopamine-responsive dystonia (DRD) with strong symptomatic responses to anti-cholinergic drugs, to assess changes in the prevalence and morphology of striatal cholinergic interneurons (ChIs) in a model of generalized dystonia.

Engineered D2R Variants Reveal the Balanced and Biased Contributions of G-Protein and β-Arrestin to Dopamine-Dependent Functions.

The dopamine D2 receptor (D2R), like many G-protein-coupled receptors, signals through G-protein- and β-arrestin-dependent pathways. Preferential activation of one of these pathways is termed functional selectivity or biased signaling and is a promising therapeutic strategy. Though biased signaling through D2Rs has been demonstrated, acquiring the mechanistic details of biased D2R/G-protein and D2R/β-arrestin signaling in vivo has been challenging because of the lack of techniques that specifically target these interactions in discrete cell populations.

A commentary on the utility of a new L-DOPA-responsive dystonia mouse model.

In a recent issue of Brain, we reported on the generation and characterization of a mouse model of the rare disease L-DOPA-responsive dystonia (DRD). Here, we discuss the utility of these mice for understanding broader disease processes and treatment strategies. Using specific experimental designs that either work "forward" from genetic etiology or "backward" from the symptomatic presentation, we discuss how our data and future work can be used to understand broader themes.

Delaying the onset of treadmill exercise following peripheral nerve injury has different effects on axon regeneration and motoneuron synaptic plasticity.

Transection of a peripheral nerve results in withdrawal of synapses from motoneurons. Some of the withdrawn synapses are restored spontaneously, but those containing the vesicular glutamate transporter 1 (VGLUT1), and arising mainly from primary afferent neurons, are withdrawn permanently. If animals are exercised immediately after nerve injury, regeneration of the damaged axons is enhanced and no withdrawal of synapses from injured motoneurons can be detected.

Serotonin 2A receptors differentially contribute to abuse-related effects of cocaine and cocaine-induced nigrostriatal and mesolimbic dopamine overflow in nonhuman primates.

Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents.

Effects of treadmill training on functional recovery following peripheral nerve injury in rats.

Exercise, in the form of moderate daily treadmill training following nerve transection and repair leads to enhanced axon regeneration, but its effect on functional recovery is less well known. Female rats were exercised by walking continuously, at a slow speed (10 m/min), for 1 h/day on a level treadmill, beginning 3 days after unilateral transection and surgical repair of the sciatic nerve, and conducted 5 days/wk for 2 wk. In Trained rats, both direct muscle responses to tibial nerve stimulation and H reflexes in soleus reappeared earlier and increased in amplitude more rapidly over time than in Untrained rats.