Molecular profiling of striatonigral and striatopallidal medium spiny neurons past, present, and future

Abstract

Defining distinct molecular properties of the two striatal medium spiny neurons (MSNs) has been a challenging task for basal ganglia (BG) neuroscientists. Identifying differential molecular components in each MSN subtype is crucial for BG researchers to understand functional properties of these two neurons. The two MSN populations are morphologically identical except in their projections through the direct verses indirect BG pathways and they are heterogeneously dispersed throughout the dorsal striatum (dStr) and nucleus accumbens (NAc). These characteristics have made it difficult for researchers to distinguish and isolate these two neuronal populations thereby hindering progress toward a more comprehensive understanding of their differential molecular properties. Researchers began to investigate molecular differences in the striatonigral and striatopallidal neurons using in situ hybridization (ISH) techniques and single cell reverse transcription-polymerase chain reaction (scRT-PCR). Currently the field is utilizing more advanced techniques for large-scale gene expression studies including fluorescence activated cell sorting (FACS) of MSNs, from which RNA is purified, from fluorescent reporter transgenic mice or use of transgenic mice in which ribosomes from each MSN are tagged and can be immunoprecipitated followed by RNA isolation, a technique termed translating ribosomal affinity purification (TRAP). Additionally, the availability of fluorescent reporter mice for each MSN subtype is allowing, scientists to perform more accurate histology studies evaluating differential protein expression and signaling changes in each cell subtype. Finally, researchers are able to evaluate the role of specific genes in vivo by utilizing cell type-specific mouse models including Cre driver lines that can be crossed with conditional overexpression or knockout systems. This is a very exciting time in the BG field because researchers are well equipped with the most progressive tools to comprehensively evaluate molecular components in the two MSNs and their consequence on BG functional output in the normal, diseased, and developing brain.