Developmental Alterations in Motor Coordination and Medium Spiny Neuron Markers in Mice Lacking PGC-1α

Abstract

Accumulating evidence implicates the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) in the pathophysiology of Huntington Disease (HD). Adult PGC-1α −/− mice exhibit striatal neurodegeneration, and reductions in the expression of PGC-1α have been observed in striatum and muscle of HD patients as well as in animal models of the disease. However, it is unknown whether decreased expression of PGC-1α alone is sufficient to lead to the motor phenotype and striatal pathology characteristic of HD. For the first time, we show that young PGC-1α −/− mice exhibit severe rotarod deficits, decreased rearing behavior, and increased occurrence of tremor in addition to the previously described hindlimb clasping. Motor impairment and striatal vacuolation are apparent in PGC-1α −/− mice by four weeks of age and do not improve or decline by twelve weeks of age. The behavioral and pathological phenotype of PGC-1α −/− mice can be completely recapitulated by conditional nervous system deletion of PGC-1α, indicating that peripheral effects are not responsible for the observed abnormalities. Evaluation of the transcriptional profile of PGC-1α −/− striatal neuron populations and comparison to striatal neuron profiles of R6/2 HD mice revealed that PGC-1α deficiency alone is not sufficient to cause the transcriptional changes observed in this HD mouse model. In contrast to R6/2 HD mice, PGC-1α −/− mice show increases in the expression of medium spiny neuron (MSN) markers with age, suggesting that the observed behavioral and structural abnormalities are not primarily due to MSN loss, the defining pathological feature of HD. These results indicate that PGC-1α is required for the proper development of motor circuitry and transcriptional homeostasis in MSNs and that developmental disruption of PGC-1α leads to long-term alterations in motor functioning.

Hypothalamic PGC-1α Protects Against High-Fat Diet Exposure by Regulating ERα

“…These data, however, contradict previously published studies of total body PGC-1α knockout mice, as well as neuronal inactivation of PGC-1α where reduced PGC-1α expression protected against diet-induced obesity (Lin et al, 2004; Ma et al, 2010). In those studies, PGC-1α deficiency led to degenerative lesions in the brain that worsened with age (Lin et al, 2004; Lucas et al, 2012; Ma et al, 2010). PGC-1α regulates a host of genes and in both of these published models PGC-1α was knocked down during development, likely provoking developmental compensations that could explain the lean phenotype.…”

PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice

“…Our findings now demonstrate that muscle‐intrinsic changes triggered by PGC‐1α are sufficient to affect motor coordination and balance in old mice. Prior work revealed that central nervous system‐specific expression of PGC‐1α is essential for motor function (Lucas et al., 2012; Zhao et al., 2011). Our present data would suggest that skeletal muscle possibly initiates a retrograde signaling to the nervous system with a similar outcome, but further studies would be needed to test this hypothesis.…”

Mice lacking the transcriptional coactivator PGC-1α exhibit alterations in inhibitory synaptic transmission in the motor cortex

“…Since the discovery of PGC-1α in 1998 (Puigserver, Wu et al 1998), many studies have suggested that a reduction in its levels and/or activity plays a role in neurological disorders including Parkinson Disease (Zheng, Liao et al 2010), Alzheimer Disease (Qin, Haroutunian et al 2009, Sheng, Wang et al 2012), Huntington Disease (Cui, Jeong et al 2006, Taherzadeh-Fard, Saft et al 2009, Chaturvedi, Calingasan et al 2010), schizophrenia (Christoforou, Le Hellard et al 2007, Jiang, Rompala et al 2013), anxiety disorders (Hettema, Webb et al 2011) and multiple sclerosis (Witte, Nijland et al 2013). Studies with whole body and neuron-specific PGC-1α −/− mice indicate that PGC-1α is required for the expression of a subset of metabolic and neuronal transcripts (Lin, Wu et al 2004, Lucas, Markwardt et al 2010, Ma, Li et al 2010, Lucas, Dougherty et al 2012), but the physiological consequences of these transcriptional changes are not clear. Elucidating the impact of PGC-1α deficiency on neuronal function will give us insight into its contribution to neuronal dysfunction in various disorders.…”