In vivo analysis of cell-autonomous versus non-cell-autonomous contributions to neuronal dysfunction in disorders of the basal ganglia

Timothy B Brown, Thomas Jefferson University


The basal ganglia are a collection of interconnected subcortical structures that are involved in the regulation of a multitude of neurological functions including motor control, emotion and cognition. Accordingly, diseases that affect the basal ganglia display a range of clinical manifestations. Huntington's disease (HD) is an adult onset fatal neurodegenerative disease caused by an expanded polyglutamine tract in the ubiquitously-expressed huntingtin protein. Despite widespread expression of the disease-causing protein, HD is characterized by selective degeneration of specific neuronal populations particularly in the cortex and striatum. Demonstrating the most striking vulnerability are the striatal medium spiny neurons (MSNs), a key component of the basal ganglia circuitry. The pathogenic mechanisms underlying this neuronal specificity remain unclear. Using a novel promoter (D9) to restrict forebrain expression to the MSNs, we have developed transgenic mice to investigate the cell-autonomous effects of mutant huntingtin expression. These mice develop MSN nuclear inclusion bodies, altered striatal gene expression and progressive motor dysfunction. These data demonstrate that several features of human HD can be recapitulated in a transgenic mouse lacking neocortical expression. A second mouse model utilizing the D9 promoter to selectively delete the tropomyosin-related kinase B (trkB) receptor on MSNs in the postnatal forebrain was generated to investigate the role of brain-derived neurotrophic factor (BDNF)/trkB signaling in striatum. These mice display a number of striatal expression changes also observed in human HD. Collectively, these mouse models suggest that both cell-autonomous transcriptional dysregulation and reduced BDNF/trkB signaling may contribute to the altered striatal gene expression profile in HD. Demonstrating that this approach can be used to study other neurological disorders of the basal ganglia caused by ubiquitously-expressed proteins, a third transgenic mouse was developed using D9 to direct expression of the mutant protein (ΔE-torsinA) causing early-onset torsion dystonia (EOTD). This model will allow an investigation of the role of the MSN in the abnormal nigrostriatal dopamine transmission observed in EOTD. Thus, the mouse models developed here provide tools to perform in vivo analysis of cell-autonomous contributions to MSN dysfunction in disorders of the basal ganglia.

Subject Area

Molecular biology|Neurosciences|Biochemistry

Recommended Citation

Brown, Timothy B, "In vivo analysis of cell-autonomous versus non-cell-autonomous contributions to neuronal dysfunction in disorders of the basal ganglia" (2010). ETD Collection for Thomas Jefferson University. AAI3416525.