These mice lack the exon 41 in the LRRK2 gene, which causes a frame shift and the introduction of an early stop codon. The animals described here are homozygous knockout mice.
Endogenous LRRK2: No
Corresponding human genotype: LRRK2 is the greatest known genetic contributor to Parkinson’s disease.
Targeted gene: LRRK2
- Absence of LRRK2 expression confirmed by PCR, northern and Southern blots (whole brain extract) and western blot and immunohistochemistry (in cortex and striatum).
- 16–20 months: No visible neurodegeneration (haematoxylin-eosin staining). In more details: no differences are observed in stereological counts of TH-positive neurons or dendrites between KO animals and control littermates. Similarly, the number of medium spiny neurons’ spines is similar in the striatum of transgenic and wild type mice. Cell proliferation in the hippocampal dentate gyrus is unaltered.
- 10, 18 and 20 months: The levels of striatal DA and its metabolites (DOPAC or HVA) are similar to those observed incontrol littermates, even after treatment with D2 receptors antagonists raclopride (HPLC, microdialysis). Similarly, striatal DA re-uptake observed in the KO mice is comparable to that of wild type animals (radioactive DA uptake assay). No differences in D1 or D2 receptors expression (autoradiography) are visible in the striatum of KO compared to wild type mice.
- Up to 18 months: No differences are observed in alpha-synuclein or tau expression (immunostaining) between KO mice and control littermates.
- 3-6 months: No significant differences are observed in the open field or cylinder tests.
- 7 and 16 months: Transgenic animals perform better on the accelerating rotarod than the control mice (only tested at 7 months). However, no difference is observed on the gait analysis. Similarly, no differences in walking distance, walking speed or onset of exploration between KO and wild-type mice in the open field. However, the transgenic animals spend significantly less time exploring the centre of the field (at both 7 and 16 months) and exhibit less convoluted path than their control littermates (only at 16 months).
Response to dopaminergic treatment
- Not reported
- 3-6 months: Memory and cognitive abilities seem unaltered, as the performances of the KO mice do not differ from those of the control animals on the novel object location and novel object recognition tests.
- 7 and 16 months: KO mice show longer delays before approaching an object placed in the centre of the open field (significant at both 7 and 16 months) and spend less time exploring it (only significant at 16 months).
- 3-6 months: No significant alterations in membrane properties of medium spiny neurons are observed in KO animals. Similarly, no changes in short-term plasticity, spontaneous excitatory postsynaptic currents or intrastriatal-evoked glutamatergic currents are observed in KO mice compared to control littermates.
- Up to 18 months: No differences are observed in activated glia (Iba1) staining between KO mice and control littermates.