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: Rockenstein 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).

2 thoughts on “Thy1-hsynwt – Mouse

    1. parkinsonuser Post author

      Line 61 mice, expressing the human wt alpha-synuclein under the TH1 promoter, have been developed by Eliezer Lasliah at UCSD. The model has also been extensively characterized in the group of Marie-Francoise Chesselet. Both publication have a pubmed link in the model page. You may want to contact one of those two groups to check on model availability.
      A different line (Line 15 expressing the wt alpha-synuclein under the Thy1 promoter developed in collaboration with the MJFF is commercially available at the Jackson Laboratory)

      Reply

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