Thy1-hsynwt – Mouse – JPND Neurodegenerative Disease Research

General Information

Mouse: CB57BL/6 /DBA2 line 61

Expression of the human wild type alpha-synuclein protein under the control of the Thy1 promoter

Endogenous mouse alpha synuclein: Yes

Corresponding human genotype: gene triplication in familial PD; polymorphism in the noncoding region of the alpha-synuclein locus leading to protein overexpression in PD patients.

Transgene insertion: X chromosome (leading to differences between males and females)

References: Roc kenstein 2002; Chesselet 2012

Transgene expression

Random inactivation of the X chromosome carrying the mutation in females makes males a better experimental model for this transgenic mouse model.

Expression of alpha-synuclein is observed starting at P10.
Expression of alpha-synuclein is observed in most brain regions (neurons) and peripheral nervous system with 2-3 fold increase compared to wild type littermates.
No expression is observed in motor neurons in this line (CB57BL/6 /DBA2 line 61).

Neurodegeneration

14 months: Very moderate loss (17%) of TH-positive terminals is detected in the striatum.
No loss of TH-positive neurons in the SN is observed at any age.
8 months: Moderate loss of TH-positive neurons is observed in myenteric neurons
Treatment of these mice with paraquat induces nigrostriatal neurodegeneration that is however not different compared to that observed in wild type mice.

Dopamine Homeostasis

6 months: Increased levels of dopamine are observed. The clearance of dopamine is not affected
8-12 months: Normal levels of dopamine and metabolites are observed
14 months: 40% loss of dopamine levels are detected

Inclusions

A progressive pattern of inclusions is observed with an increase in size and number of aggregates in aged mice.

1 months: Small inclusions are observed in the dorsal nucleus of the vagus and the olfactory bulb; large inclusions are detected in the thalamus, locus coereleus and cerebellum.
5 months: Inclusions areobserved in the SN.
No inclusion are observed in the cerebral cortex although high levels of alpha-synuclein are detected.
High levels of alpha-synuclein phosphorylated at serine 129 are detected in the mesencephalon, striatum, cortex and hippocampus principally located in the cell soma and nucleus. (Note: Phosphorylated alpha-synuclein is present in nerve terminals in wild type mice)
No inclusions are detected in myenteric neurons although they express high levels of alpha-synuclein.

Motor Behaviours

4-7 months: hyperactive mice possibly linked to elevated dopamine levels measured in the striatum (see ”Dopamine homeostasis” above)
2-8 months : early deficits are detected in challenging motor tests; these deficits increase with aging (Rotarod test, walking on beam overlaid with grid, nest building, pole test, cylinder test).
14 months: deficits are observed in normal motor tests (catalepsy in block test, reduced open field activity, slowness in sensory motor test).

Response to L-DOPA treatment

14 months :L-DOPA treatment can reverse the motor deficits.

Non motor Behaviours

Circadian rhythms alterations: reduced amplitude of rhythms and fragmentation of the rest/activity cycles (3-4 months).
Gastrointestinal alterations: reduced fecal output under stress situation (7-8 months) and colonic alterations (12 months). No changes in gastric emptying are detected between 4 and 18 months.
Olfactory alterations : high olfactory impairment (3 and 9 months).
Cognitive alterations: impairments in the Y-maze, novel-object and object-place recognition, as well as in operant reversal learning (4-6 months); increased anxiety in observed at 4 months

Electrophysiology

1-10 months: early stage déficits are detected in cortico striatal transmission indicative of early pre-synaptic dysfunctions

Neuroinflammation

Detection of early innate inflammatory response in the brain and periphery.
Microglia activation is observed in the striatum (1-14 months) and in the SN (starting at 5-6 months).