General Information

Mouse: CB57BL/6 x B6C3H

Conditional expression of the human mutant (A53T)  alpha-synuclein protein under the control of the Calcium/calmodulin-dependent protein kinase IIa promoter (CaM) and the tetracycline-regulated tet-off system (tTA).

Endogenous alpha synuclein: Yes

Corresponding human genotype: Autosomal dominant mutation in PD patients (PARK1/PARK4)

Transgene insertion:  not specified

References: Lim 2010;  Lim 2011

Transgene expression

• Expression of human alpha-synuclein is observed in forebrain and midbrain with a 1-3 x increase compared to littermate wild type mice. Some expression is detected in the cerebellum.
• The expression of human mutant alpha-synuclein can be controlled (blocked) by giving mice doxycycline in drinking water or chow.

Neurodegeneration

• Alpha-synuclein-dependent atrophy of postmitotic hippocampal DG neurons is observed at P14 (moderate) and P21 (strong).
• In mice treated with doxycycline until P21 no atrophy is observed in DG neurons until 6 months but a severe cellular loss is detected at 20-22 months.
• No loss of TH-positive neurons is observed.

Dopamine Homeostasis

• Not reported

Inclusions

• Before 4 months : no abnormal accumulation of alpha-synuclein is detected
• 4-8 months: abnormal alpha-synuclein that increases in intensity with time is observed in limbic areas .
• 12 months: elevated accumulation of abnormal alpha-synuclein is observed. This pathology can be abolished by preventing transgene expression (using doxycycline) for 3 months from 9-12 months.
• 20-22 months: cytoplasmic accumulation of alpha-synuclein is detected in limbic areas as well as in the neocortex, hippocampus and cortical regions.

Motor Behaviours

• Not reported.

Response to L-DOPA treatment

• Not reported

Non motor Behaviours

• 8 months: reduced contextual fear memory is observed in mice conditionally expressing the transgene starting at P21. Some alterations are also observed in cued fear conditioning tests. The phenotype can be reversed by treating mice with doxycycline to prevent transgene expression.

Electrophysiology

• Not reported

Neuroinflammation

• Increased astrogliosis is observed in the hippocampus. This gliosis can be reduced by preventing transgene expression using doxycycline.