Social Cognition Impairments in Mice Overexpressing Alpha-Synuclein Under the Thy1 Promoter, a Model of Pre-manifest Parkinson’s Disease

Abstract

Background: Patients with Parkinson’s disease (PD) may exhibit deficits in “Theory of Mind”, the ability to read others’ mental states and react appropriately, a prerequisite for successful social interaction. Alpha-synuclein overexpression is widely distributed in the brain of patients with sporadic PD, suggesting that it may contribute to the non-motor deficits observed in PD patients. Mice over-expressing human wild-type alpha-synuclein under the Thy1 promoter (Thy1-aSyn mice) have synaptic deficits in the frontostriatal pathway, low cortical acetylcholine, and high level of expression of mGluR5 receptors, which have all been implicated in social recognition deficits. Objective: To determine whether Thy1-aSyn mice present alterations in their response to social stimuli. Methods: We have submitted Thy1-aSyn mice to tests adapted from autism models. Results: At 7–8 month of age Thy1-aSyn mice explored their conspecifics significantly less than did wild-type littermates, without differences in exploration of inanimate objects, and pairs of Thy1-aSyn mice were involved in reciprocal interactions for a shorter duration than wild-type mice at this age. These deficits persisted when the test animal was enclosed in a beaker and were not present at 3–4 months of age despite the presence of olfactory deficits at that age, indicating that they were not solely caused by impairment in olfaction. Conclusion: Thy1-aSyn mice present progressive deficits in social recognition, supporting an association between alpha-synuclein overexpression and Theory of Mind deficits in PD and providing a useful model for identifying mechanisms and testing novel treatments for these deficits which impact patients and caretakers quality of life.

RETRACTED ARTICLE: Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease

“…Recent neuropathological studies indicate that Lewy bodies accumulation in several neuronal cell types in the brain can be used as an intraneuronal landmark of PD because LB formation has been reported widely, from the medulla oblongata and olfactory bulb to neocortical areas [ 53 ]. As such, the PD model developed here is by previously reported animal models [ 2 , 48 , 54 ] because the mutant α-syn overexpression in the olfactory bulb mimicked prodromal symptoms of PD. Further evaluation of this model may contribute to the development of the precocious diagnosis of PD and may be used in the future to test the efficacy of neuroprotective agents.…”

Impact of DHA intake in a mouse model of synucleinopathy

“…The 50% mortality rate observed in Thy1-aSyn mice fed the control or DHA-deprived diets was more important than in previous reports, where rising mortality was observed only after 14 months of age (Chesselet et al, 2012;Lam et al, 2011). It should be noted that we used Thy1-aSyn mice on a fully backcrossed C57Bl/6 background, while most publications use the hybrid C57BL/6-DBA/2 background (Chesselet et al, 2012;Lam et al, 2011;Magen et al, 2015), which may have contributed to the higher and earlier mortality rate observed here. Although we did not determine the exact causes of mortality, the protective effect of the DHA diet may relate to its multiple beneficial effects on different organs, aside from the brain, during aging (Trepanier et al, 2016).…”

A Molecular Tweezer Ameliorates Motor Deficits in Mice Overexpressing α-Synuclein

“…We used mice overexpressing human, WT α-synuclein under the murine Thy-1 promoter (Thy1-aSyn) [31], which has been characterized thoroughly in the Chesselet laboratory. This mouse model reproduces multiple features of PD including motor dysfunction, nonmotor deficits, mitochondrial dysfunction, inflammation, α-synuclein pathology, and dopamine loss [15,[32][33][34][35][36][37][38][39]. Our data show that amelioration of motor deficits following treatment with CLR01 associates with clearance of buffer-soluble α-synuclein but not insoluble α-synuclein aggregates.…”