Molecular mechanisms relevant to the maintenance of locomotor control

Thesis

The striatum, consisting of enkephalin-positive (Penk+) and substance P-positive subpopulations of medium spiny neurons (MSNs), integrates and drives information and function of the basal ganglia circuits, which is crucial for maintaining normal movement. Preferential degeneration of the Penk+ MSNs has been observed at early stage of Huntington disease (HD). Recently, selective deletion of TrkB, high affinity receptor of brain derived neurotrophic factor (BDNF), specifically in the Penk+ MSNs (TrkbPENK-KO) led to an age-dependent spontaneous hyperlocomotion, but not to neuronal loss, indicating that TrkB is essential to maintain normal locomotor control. However, the underlying molecular mechanism still remains unknown. Dissecting the molecular changes induced in the Penk+ MSNs in the context of absence of TrkB is imperative to understand mechanism of normal locomotor maintenance. We, therefore, have performed transcriptomics analysis by next generation sequencing (RNA-seq) on the purified Penk+ MSNs with and without ablation of TrkB at two ages. Subsequent bioinformatics analysis has revealed early energy metabolism and mitochondrial dysfunction specifically to the Penk+ MSNs, leading to the severe energy deficiency at later stage. We have then validated hits from the RNA-seq data by optimising comprehensive validation approaches. Interestingly, the bioinformatics analysis led to the discovery of dopamine dysregulation in mutants at early age that could contribute to an age-dependent hyperlocomotor phenotype. Amongst the hits we validated, an enzyme involved in the glutathione metabolism, was identified as a key gene with unique expression pattern driving transcriptomic changes of the Penk+ MSNs. Furthermore, by creating a Cre-dependent shRNA lentiviral vector, we selectively knocked down specific gene expression in the Penk+ MSNs in vivo at presymptomatic age. Excitingly, this significantly rescued the hyperlocomotor phenotype of the Trkb^PENK-KO mice. These findings add knowledge to the molecular mechanisms underlying normal locomotor maintenance, and they also highlight related pathway as a potential target for the development of novel treatments to movement disorders.

Authors: Guo, F

• DOI: 10.5287/ora-nrzopkdxn
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Striatum; locomotor behavior; Enkephalinergic neurons
• Subjects: Neurosciences; Molecular neuroscience