The neurobiological basis for novel experimental therapeutics in dystonia.

Dystonia is a movement disorder characterized by involuntary muscle contractions, twisting movements, and abnormal postures that may affect one or multiple body regions. Dystonia is the third most common movement disorder after Parkinson's disease and essential tremor. Despite its relative frequency, small molecule therapeutics for dystonia are limited. Development of new therapeutics is further hampered by the heterogeneity of both clinical symptoms and etiologies in dystonia. Recent advances in both animal and cell-based models have helped clarify divergent etiologies in dystonia and have facilitated the identification of new therapeutic targets. Advances in medicinal chemistry have also made available novel compounds for testing in biochemical, physiological, and behavioral models of dystonia. Here, we briefly review motor circuit anatomy and the anatomical and functional abnormalities in dystonia. We then discuss recently identified therapeutic targets in dystonia based on recent preclinical animal studies and clinical trials investigating novel therapeutics.

Striatal Subregion-selective Dysregulated Dopamine Receptor-mediated Intracellular Signaling in a Model of DOPA-responsive Dystonia.

Although the mechanisms underlying dystonia are largely unknown, dystonia is often associated with abnormal dopamine neurotransmission. DOPA-responsive dystonia (DRD) is a prototype disorder for understanding dopamine dysfunction in dystonia because it is caused by mutations in genes necessary for the synthesis of dopamine and alleviated by the indirect-acting dopamine agonist l-DOPA. Although adaptations in striatal dopamine receptor-mediated intracellular signaling have been studied extensively in models of Parkinson's disease, another movement disorders associated with dopamine deficiency, little is known about dopaminergic adaptations in dystonia. To identify the dopamine receptor-mediated intracellular signaling associated with dystonia, we used immunohistochemistry to quantify striatal protein kinase A activity and extracellular signal-related kinase (ERK) phosphorylation after dopaminergic challenges in a knockin mouse model of DRD. l-DOPA treatment induced the phosphorylation of both protein kinase A substrates and ERK largely in D1 dopamine receptor-expressing striatal neurons. As expected, this response was blocked by pretreatment with the D1 dopamine receptor antagonist SCH23390. The D2 dopamine receptor antagonist raclopride also significantly reduced the phosphorylation of ERK; this contrasts with models of parkinsonism in which l-DOPA-induced ERK phosphorylation is not mediated by D2 dopamine receptors. Further, the dysregulated signaling was dependent on striatal subdomains whereby ERK phosphorylation was largely confined to dorsomedial (associative) striatum while the dorsolateral (sensorimotor) striatum was unresponsive. This complex interaction between striatal functional domains and dysregulated dopamine-receptor mediated responses has not been observed in other models of dopamine deficiency, such as parkinsonism, suggesting that regional variation in dopamine-mediated neurotransmission may be a hallmark of dystonia.

Hatching asynchrony impacts cognition in male zebra finches.

Conditions experienced early in life can shape brain development and later cognition. Altricial songbirds are particularly vulnerable to early environmental perturbations. Research on "Developmental Stress" in songbirds has addressed how early-life conditions may impair song learning and has been extended to consider other components of adult phenotype. Early-life challenges ranging from ectoparasites to competition with siblings have been shown to compromise song learning and other measures of cognition, as well as behavioral strategy. Here, we examined both the effects of hatching asynchrony and early-life immune system challenge with lipopolysaccharide (LPS) on neophobia, song learning, motoric learning, and spatial cognition in male zebra finches (Taeniopygia guttata). We found that hatch order had a significant impact on motoric and spatial learning, such that later hatched males performed better than first and second hatched birds. In contrast, LPS treatment only impacted motoric learning and neither hatch order nor immune system challenge impacted song quality, song learning accuracy, or neophobia. These results are consistent with a growing body of evidence that conditions early in life can improve cognitive performance at adulthood. Moreover, these findings indicate that hatch order is an important factor to consider in developmental studies in asynchronously hatching birds.