Preliminary Evidence of Apathetic-Like Behavior in Aged Vesicular Monoamine Transporter 2 Deficient Mice

Abstract

Apathy is considered to be a core feature of Parkinson's disease (PD) and has been associated with a variety of states and symptoms of the disease, such as increased severity of motor symptoms, impaired cognition, executive dysfunction and dementia. Apart from the high prevalence of apathy in PD, which is estimated to be about 40%, the underlying pathophysiology remains poorly understood and current treatment approaches are unspecific and proved to be only partially effective. In animal models, apathy has been sub-optimally modeled, mostly by means of pharmacological and stress-induced methods, whereby concomitant depressive-like symptoms could not be ruled out. In the context of PD only a few studies on toxin-based models (i.e., 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)) claimed to have determined apathetic symptoms in animals. The assessment of apathetic symptoms in more elaborated and multifaceted genetic animal models of PD could help to understand the pathophysiological development of apathy in PD and eventually advance specific treatments for afflicted patients. Here we report the presence of behavioral signs of apathy in 12 months old mice that express only ~5% of the vesicular monoamine transporter 2 (VMAT2). Apathetic-like behavior in VMAT2 deficient (LO) mice was evidenced by impaired burrowing and nest building skills, and a reduced preference for sweet solution in the saccharin preference test, while the performance in the forced swimming test was normal. Our preliminary results suggest that VMAT2 deficient mice show an apathetic-like phenotype that might be independent of depressive-like symptoms. Therefore VMAT2 LO mice could be a useful tool to study the pathophysiological substrates of apathy and to test novel treatment strategies for apathy in the context of PD.

Keywords: PD mice; apathy; depression; goal-directed behaviors; vesicular monoamine transporter 2.

Figure 1

Decreased burrowing activity in vesicular monoamine transporter 2 (VMAT2) deficient mice. Burrowing activity was determined 2 h (A–C) and one night (D–F) after the test start in both LO mice and their WT controls. No differences were found in the whole (n = 19 WT, n = 15 LO; A,D) or proficient (n = 10 WT, n = 8 LO; B,E) burrower populations. In the poor burrower population, the percentage of burrowed material of LO mice was not significantly different from WT mice (n = 9 WT, n = 6 LO; ^§p = 0.055; C) after 2 h. However, the percentage of burrowed material was significantly reduced in LO mice (n = 8 WT, n = 7 LO; *p < 0.05; F) for the overnight period. Bars indicate the mean of the groups and error bars indicate the S.E.M. ^§Indicates a non-significant trend.

Figure 2

Impaired nesting in VMAT2 deficient mice. Nesting performance was assessed by measuring the percentage of the Nestlet torn (A–C) and the nest rating (score 1–5; D–F) in both LO mice and their WT controls. No differences were found in the whole (n = 19 WT, n = 15 LO; A,D) or inactive (n = 9–10 WT, n = 5–7 LO; C,F) nester populations. However, both the % of Nestlet torn and the nest rating scores were significantly reduced in the LO group within the active nesters population, as compared to their WT controls (percentage of Nestlet torn: n = 9 WT, n = 8 LO, *p < 0.05, (B) nest ratings: n = 10 WT, n = 10 LO, **p < 0.01, E). Bars indicate the mean of the groups and error bars indicate the S.E.M.

Figure 3

Reduced preference for a sweetened solution in VMAT2 deficient mice. The amount of water (A) saccharin (B) and total liquid (C) intake was determined by the saccharin preference test. In addition, we calculated (D) the saccharin preference ratio as the intake of (saccharin/(saccharin + water)). There was no difference in water intake between LO and WT mice. However, saccharin and total liquid intake (driven by the reduction in saccharin intake) was significantly reduced in LO mice, as compared to their WT controls (saccharin intake **p < 0.01, total liquid intake *p < 0.05). A significantly reduced saccharin preference ratio was also driven by the pronounced reduction in saccharin consumption (p < 0.05). All measures were normalized by the respective body weight to control for the lower weight of the VMAT2 mutants. Bars indicate the mean of the groups and error bars indicate the S.E.M.

Figure 4

Normal immobility time in VMAT2 deficient mice. The time of immobility during a forced swimming session of 4 min in WT and LO mice indicated no significant differences between both genotypes in the whole and the two sub-populations analyzed. Two-sided, t test; (A) whole population: p = 0.896; (B) proficient swimmers: p = 0.742; (C) poor swimmers: p = 0.777. Bars indicate the means of the groups and error bars indicate the S.E.M.