The exon 3 of the Parkin gene is altered, either through insertion of the coding sequence of the EGFP or a 1097 bp deletion, leading in both cases to the introduction of an early stop codon.
The animals described here are homozygous KO mice.
Endogenous Parkin: No
Corresponding human genotype: The exon 3 deletion results in the absence of Parkin protein and is one of the most common mutations found in autosomal recessive juvenile parkinsonism.
Targeted gene: Parkin
The absence of Parkin expression confirmed by western blot.
Up to 24 months: In most of cases, no visible degeneration is observed in the SN or striatum of the Parkin KO mice compared to control littermates. One of the studies reports a significant loss of TH- positive neurons in the SN and a drop in the density of the striatal projections at 24 months, more pronounced in the female mice.
6, 12, 18 and 24 months: Levels of striatal DA and its metabolites (DOPAC or HVA) are similar to those measured in the control mice (HPLC); the level of extracellular DA seems higher in the striatum of KO mice compared to the wild type animals (dialysate following perfusion with DA-free artificial CSF 8-9 months).
Total DA receptor binding (D1 and D2) and of 5-HT levels are unaltered.
The levels of DA transporter (DAT) and VMAT2 are lower in the striatum of KO mice.
Up to 24 months: No alpha-synuclein or ubiquitin positive inclusions are observed. A significant increase in soluble and insoluble tau is measured in the striatum and hippocampus of KO animals.
Up to 7 months: The Parkin KO mice perform significantly worse that the control littermates during the beam transversal task and the adhesive removal task. Performance of the KO animals on the rotarod and pole tests are comparable to those of wild type mice
18 months: the length of step strides performed by the KO animals is significantly smaller than the step strides of control mice
Up to 24 months: Most studies show that no significant alterations are observed in the open field test. One study reports reduced exploratory behaviour in the open field.
Response to dopaminergic treatment
5-6 months: KO animals do not show sign of habituation when placed repetitively in the same open field. They are less curious about the unknown arm of the T-maze and exhibit lower recognition index in the object location task compared to wild type animals, indicative of altered memory functions.
3, 6 and 9 months: Striatal medium spiny neurons are less excitable synaptically in KO animals than in the wild type animals. The maximum amplitude of the evoked DA overflow is lower in young transgenic animals compared to the wild type (only significant at 3 and 6 months).
Controversial data have been reported concerning the ability to induce long-term potentiation in hippocampal slices. Both a slight increase in paired pulse facilitation and reduced amplitude of the excitatory post-synaptic potential are observed.
24 months: Glial activation is comparable between the transgenic and wild type mice (immunostaining against astrocyte and microglia markers).