General Information

Mice: C57BL/6J or FVB

Expression of the full-length human wild type LRRK2 protein using the bacterial artificial chromosome (BAC).

Endogenous LRRK2: yes

Corresponding human genotype: LRRK2 is the greatest known genetic contributor to Parkinson’s disease.

Targeted gene: LRRK2

References:

FVB: Li 2009, Merlose 2010, Winner 2011

C57BL/6J: Beccano-Kelly 2015

Transgene expression

C57BL/6J:

  • 3 months: Overall transgene expression in the striatum and cortex is about 1.5-3 fold higher than the endogenous LRRK2.

FVB:

  • Overall human transgene expression is about 3.5 fold higher than the endogenous mouse LRRK2 in the brain of the transgenic animals (although it is much higher in the hippocampus: 20 fold). Anatomical expression patterns are similar to the endogenous mouse gene but the level of the protein is increased.

Neurodegeneration

C57BL/6J:

  • 6 months: No differences in the levels of striatal TH, dopamine receptor D1 or DARPP-32 proteins. However, striatal level of DA receptor D2 is elevated in the transgenic mice.

FVB:

  • 22-24 months: No differences are detected in the number of TH-positive cells in the SN.

Dopamine Homeostasis

C57BL/6J:

  • 3-6 months: In vivo striatal levels of dopamine (DA) are significantly lower in transgenic animals compared to control littermates at baseline. A non-significant decreasing trend in the levels of DA metabolites (DOPAC, HVA) is observed in the striatum (in vivo microdialysis). DA reuptake abilities remain unaltered.

FVB:

  • 18 months: In vivo striatal levels of DA are significantly lower in transgenic animals compared to control littermates at baseline (striatal microdialysis). No differences are observed after amphetamine injection Note that no differences in the level of DA or its metabolites (DOPAC, HVA) are observed in the striatum of the transgenic mice post-mortem (HPLC). A modest increase in the number of striatal dopamine D1 (significant) and D2 (non-significant) receptors density is observed.

Inclusions

C57BL/6J:

  • Not reported

FVB:

  • Up to 24 months: No abnormalities can be seen with alpha-synuclein, phosphorylated alpha-synuclein or phosphorylated tau staining.

Motor Behaviours

C57BL/6J:

  • Over 6 months: A significant reduction of the total exploratory and ambulatory time can be observed in the open field. Similarly, the number of spontaneous rearing events performed by the transgenic animals in the cylinder test is lower than the one reported for the control mice.

FVB:

  • 22-24 months: No significant changes are observed during motor assessments (open field, beam crossing test, inked footprint analysis, negative geotaxis test).

Response to dopaminergic treatment

C57BL/6J:

  • 3-6 months: Systemic administration of D2 receptor agonist (pramipexole) or antagonist (remoxipride) does not produce any behavioural effect (open field and cylinder). Treatment with remoxipride (ex vivo) reversed the deficit in short-term plasticity observed in transgenic animals (see Electrophysiology below).

FVB:

  • 18 months: No differences are observed the DA/metabolites striatal ratio changes and stored DA induced by treatment with the D2 receptor antagonist raclopride.

Non-motor Behaviours

C57BL/6J:

  • Over 6 months:  The performances of the transgenic mice do not differ from those of control non transgenic animals on the novel object location or the novel object recognition tests during short term memory assessments (5min intervals). However, the animals fail to recognise a new object after longer intervals (24h).

FVB:

  • Not reported

Electrophysiology

C57BL/6J:

  • 3-6 months: No significant alterations in membrane properties of medium spiny neurons are observed in transgenic animals. Similarly, no changes in spontaneous excitatory postsynaptic currents or intrastriatal-evoked glutamatergic currents are observed in transgenic mice compared to control littermates. However, a reduction in short-term plasticity of striatal neurons can be observed in the transgenic mice.

FVB:

  • Not reported

Neuroinflammation

C57BL/6J:

  • Not reported

FVB:

  • 18-24 months: No visible changes are observed in activated microglia (Iba-1 immunostaining).