Mouse: Originally in 129/Sv-SL mice; crossed and maintained on C57BL/6
Mice with a homozygous disruption in the promoter region of the Pitx3 homeogene leading to loss of protein expression (Pitx3-/-).
Corresponding human genotype: Single nucleotide polymorphisms (SNP) in the Pitx3 gene may represent a higher risk of developing Parkinson’s disease in certain ethnic populations.
Mutated gene: Pitx3
References: van den Munckhof 2003, Smits 2005, van den Munckhof 2006; Ardayfio 2008; Le 2015
Loss of dopaminergic neurons
- E12.5: the number of TH-positive cells is comparable in mesencephalic neurons of aphakia and wild type mice.
- P1: significant loss of TH-positive neurons is observed in the SN but not the VTA.
- 7 weeks: complete absence of Pitx3 expression is evidenced in mesencephalic neurons
- 14 weeks: significant reduction of TH-positive neurons (72%) is observed in the SN , with the exemption of the dorsal tier of the SN (dSNc), as well as in the VTA (52%). Interestingly, in wild type mice TH-positive neurons in the dSNc do not express Pitx3. This indicates the existence of different subpopulations of TH-positive neurons in the SN that display different intrinsic requirements (presence of PitX3) for survival.
Sparing of dSNc in the mutant mice is reminiscent of observations in PD brain samples.
- 14 weeks: a drastic reduction of dopamine levels is observed in the dorsal (93%; receiving SN projections) and ventral striatum (69%; receiving VTA projections).
- 5-6 months: a dramatic decrease in dopamine release is detected.
- Not reported
- 1 months and 4 weeks: a reduction in ambulatory and stereotypic activities is observed during the night , reminiscent of PD akinesia; no reduction is detected during the day. This reduction is not due to the blindness associated with the mutation.
- 3-5 months: poor motor performance on rotarod and reduced locomotor (total distance traveled) activities are observed
Response to dopaminergic treatment
- 1 months: Impaired night motor activity can be rescued by acute L-DOPA treatment
Non motor Behaviours
- Social transmission of food preference: this task is thought to involve cholinergic circuit in the brain and is normal in aphakia mice.
- Avoidance learning: the change in latency to avoid a shock is reduced in mutant mice, indicating an impaired memory for the shock.
- Swimming T-maze: after training aphakia mice display an increased latency to find the platform suggesting an impairment in procedural learning. Because this test is physically demanding and may be influenced by motor impairments the dry, food-motivated T-maze was also performed (see below).
- Dry T-maze : aphakia mice do not learn where the food is located with training. This observation confirms the swimming T-maze data and indicates a reduced procedural learning capacity.
- Anhedonia: depression-like symptoms, evidenced using the sucrose preference test is observed in aphasia mice (10-16 weeks). This symptom is reversed by chronic treatment with an anticholinergic antidepressant (imipramine).
- 3-5 months: fast-scan cyclic voltametric measurement indicate that the peak magnitude of the single pulse-evoked dopamine signal is 92% smaller in aphakia mice compared with control mice .
- Not reported