Involvement of Foxp2 in the alterations of the basal ganglia circuitry in Huntington’s Disease

Abstract

[eng] Huntington’s Disease (HD) is an autosomal dominant inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive manifestations. The disease is caused by an unstable expansion of the CAG trinucleotide repeat in the huntingtin gene (Htt), which eventually leads the HD patients to death, in a period of a few decades. Regardless the ubiquitous expression of mutant huntingtin (mHtt) in somatic tissues, the pathologic features are seemingly restricted to the brain. During the disease, the caudate and putamen (striatum in mice) suffers a progressive neuronal loss and atrophy. Later, other brain regions as cortex and hippocampus also become affected as the neuronal loss and atrophy are widely spread throughout the brain. As striatum is the main hub of basal ganglia circuit, which orchestrates the voluntary motor sequences along with cognitive and emotional responses, it is believed that striatum pathophysiology underlies the behavioral symptoms of the disease. Importantly, before neurodegeneration mHtt acts from the roots of cellular processes inducing the synaptic and neuronal dysfunction of the striatal neurons until death. Hence, we believed in the importance of deciphering the initial and triggering key mechanisms of the disease in prodromal stages and designing useful therapeutic strategies able to delay the onset of the neuropathologic changes and clinical symptoms in HD. Here, we identify a candidate gene named Foxp2, which has been shown to be strongly associated with basal ganglia circuitry in conjunction with psychiatric and motor deficits. We identified an early striatal downregulation of Foxp2 protein which seems to be linked to behavioral and molecular changes in the juvenile R6/1 mouse model. Juvenile R6/1 mice behavioral phenotype was characterized by an increased hyperlocomotive and impulsive-like behavior, less aggressive-like behavior and disrupted locomotor circadian rhythms concomitant with structural and functional changes as decreased dendritic spine density and dysregulation of striatal protein expression. Interestingly, the rescue of striatal Foxp2 levels reverted impulsivity-phenotype, likely by rescuing striatal protein expression dysregulation and synaptic plasticity impairment. We also detected a downregulation of Foxp2 protein in the thalamus of pre- and symptomatic R6/1 mouse. We confirmed the well-established cortico- striatal disconection previously found in HD models, but we also demonstrated the functional disconnection between the thalamus and the striatum at symptomatic stages of R6/1 mice. Recovery of Foxp2 in the ventrolateral thalamus rescued sensory-motor behavioral disturbances in the symptomatic R6/1 mice, along with structural and functional changes, whereas knockdown of Foxp2 mimicked HD-associated phenotype. In summary, our study points out Foxp2 as a potential target to understand the neuropathogenesis and behavioral deficits in HD.