Mice expressing the A53T mutant form of human alpha‐synuclein exhibit hyperactivity and reduced anxiety‐like behavior

Abstract

Genetic mutations associated with α-synuclein (α-Syn) are implicated in the pathogenesis of Parkinson's disease (PD). PD is primarily a movement disorder, but patients are known to experience anxiety and other mood disorders. In this study, we examined the effect of the hA53T mutation during development by analyzing the protein expression of norepinephrine (NET), serotonin (SERT), and dopamine (DAT) transporters in addition to assessing locomotor and anxiety-like behavior. We observed significant decreases in DAT expression at 8 months in transgenic animals compared with normal and younger mice. We used the elevated plus maze, open-field test, and rotarod apparatus to evaluate wild-type and hA53T hemizygous mice at 2, 8, and 12 months of age. Our results showed that 12-month-old transgenic mice spend more time in the open arms and display a greater number of open entries of the elevated plus maze compared with wild-type controls and younger mice. Open-field test results showed that 12-month-old mice travel a greater distance overall and travel more in the inner zone than either wild-type or younger mice. Rotarod testing showed that 8-and 12-month-old transgenic mice perform better than either wild-type controls or younger mice. Overall, 8-12-month-old transgenic mice showed a trend toward reduced anxiety-like behavior and increased hyperactivity. These results indicate a possible role of the A53T α-Syn mutation in anxiety-like and hyperactive behaviors in a PD mouse model, suggesting that these behaviors might be comorbid with this disease. Keywordsbehavior; dopamine transporter; anxiety disorders; Parkinson's disease Parkinson's disease (PD) is a common neurodegenerative movement disorder affecting approximately 1% of the elderly population. Clinical manifestations reflect a loss of dopaminergic (DA) neurons in the substania nigra pars compacta and include bradykinesia, resting tremor, stiffness, postural instability, and periods of freezing (Simuni and Hurtig, 2000). One of the most common histopathological features of PD is the Lewy body (LB), a proteinaceous fibrillar cytoplasmic inclusion present in the neuronal perikarya. Recent evidence shows that the main components of LB's are amyloid-like fibrils composed of αsynuclein (α-Syn) protein. α-Syn is a small acidic protein (~14 kD) composed of 140 amino acids and is expressed predominantly in the presynpatic terminals, particularly in the neocortex, hippocampus, striatum, thalamus, and cerebellum (Iwai et al., 1995 . Recent biochemical studies show functional interactions between α-Syn and dopaminergic neurotransmitter system, including the regulation of dopamine synaptic availability and homeostasis, modulation of dopamine release, and synthesis and targeting of the dopamine transporter to the plasma membrane (Davidson et al., 1998;Jensen et al., 1998;Murphy et al., 2000;Abeliovich et al., 2000;Stefanis et al., 2001;Lee at al, 2001;Perez et al., 2002;Cabin et al., 2002; Wersinger et al., 2003a,b). In addition, α-Syn is involved in modulating seroton...

Age-Dependent Effects C57BL/6 Genetic Mutations under Mice Models of Parkinson’s Disease on Motor Ability

“…To determine the time process and locomotor activity of development of C57BL/6 genetic mutations, we used the open field test to assess this parameters. Previous study revealed that genetic mutations traveled significantly greater distances compared with wild-type mice at 2 months and 12 months of age [5,6,7]. In our task, we did not confirm this notion at 3-month-old mice[ Fig.…”

Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

“…1a). This hyperactive phenotype is also commonly observed at an early time point in different α-syn transgenic mouse lines [30, 34, 43, 44, 81, 92, 106]. Additionally, increased striatal TH and locomotor response is observed in olfactory bulbectomized animal models of depression, possibly owing to direct connections between the striatum and areas of the limbic system, including the olfactory bulb and amygdala [80].…”

NACP-Rep1 relates to Beck Depression Inventory Scores in Healthy Humans

“…A genetic polymorphism of SNCA is said to contribute to anxiety-like behavior in mice (Graham and Sidhu 2010). Anxiety and depression are highly comorbid and distinguishing one from the other within the animal model is difficult.…”

“…The A53T mutation is said to contribute to anxiety-like behavior and increased hyperactivity in mice (Graham and Sidhu 2010). In recent investigations, a regulatory effect on transcriptional activity has been ascribed to NACP-Rep1, a 300 bp repeat located between rs7678651 and rs7687945 about 9 kb upstream from the transcription start site of SNCA (Xia et al 1996;Chiba-Falek and Nussbaum 2001;Touchman et al 2001;Chiba-Falek et al 2003;Foroud et al 2007;Cronin et al 2009;Linnertz et al 2009; see Fig.…”