General Information

Mouse: DAT-cre x Tfam^loxP on B1/6 or CB57BL/6 background

Mice with a homozygous disruption of the mitochondrial transcription factor A (Tfam) in dopaminergic neurons leading to reduced mtDNA expression and mitochondria respiratory chain deficiency.

Corresponding human genotype: Evidence suggest a role for mitochondrial dysfunction in sporadic Parkinson’s disease.

Target gene:  mitochondrial transcription factor A (Tfam)

References: Ekstand 2007; Galter 2010; Branch 2016, Cong 2016, Li 2013, Marcellino 2010

Brain phenotype

• 30 weeks: enlarged lateral ventricles (15%) and reduced brain volume (10%) are observe. No gender différences are detected

Mitochondrial deficits

• 6 weeks – 20 weeks: reduced expression of cytochrome oxidase subunit I (COX) expression and activity is observed in midbrain dopamine neurons indicative of a reduced mtDNA expression.

Neurodegeneration

• 12 weeks: first signs of a progressive loss of dopaminergic neurons (40%) in the SN.
• 16–43 weeks: progressive loss of TH-positive neurons is observed in the SN reaching 90% loss at 43 weeks. Significant loss of TH-positive terminals is observed in the striatum.

Dopamine Homeostasis

• 6-40 weeks: significant progressive reduction of nigrostriatal dopamine levels and increased dopamine turnover (increased ratio of dopamine metabolites, DOPAC and HVA, to dopamine) are observed.
  Slow decrease of dopamine levels are detected in the Frontal cortex with a reduction of dopamine turnover
• 40 weeks: significant reduction of dopamine levels are observed in the olfactory bulb.

Inclusions

• 6-43 weeks: Cytoplasmic aggregates are observed in dopaminergic neurons. The number of aggregates diminishes but their size increases with age and with advancement of the neurodegenerative process

Motor Behaviours

• 6 weeks: Hyperactivity is detected in horizontal and vertical activity.
• 10 weeks: No apparent locomotor deficits are observed compared to control mice
• 12-15 weeks: First signs of decreased locomotion (bradykinesia) and reduced exploratory activity are detected.
• 20 weeks: Tremors and apparent limb rigidity are observed.
• 24 weeks: Significant reduction in locomotor activities are present
• 45 weeks: Poor general conditions requiring sacrifice

Response to dopaminergic treatment

• 8 weeks: L-DOPA treatment (4 or 20 mg/kg) induces a very moderate improvement in locomotion
• 16 weeks: Improved locomotor activities are observed with 20 mg/kg L-DOPA. No or little effect is observed with a low L-DOPA dose (4mg/kg).
• 24 weeks: both low and high L-DOPA doses (4 or 20 mg/kg) improve locomotion activities, the larger dose inducing a longer effect
• 32 weeks: dose-dependent effect of L-DOPA on the locomotor activities. The smaller dose (4 mg/kg) induces a high and long lasting effect while the larger dose (20 mg/kg) induces a two-peaked improvement pattern.

Response to non-dopaminergic treatment

• 12 weeks: acute treatment with an antagonist of the adenosine 2A receptor (MSX-3 5mg/kg) induces a significant increase in locomotion. This effect is lost at 22 and 32 weeks. Non-transgenic mice show a strong locomotor response to the same dose of MSX-3 at all ages.
  Chronic treatment (8 weeks) with MSX–3 prevents the decrease in spontaneous activity typically observed with aging in the transgenic mice.

Non motor Behaviours

• 8 weeks: deficits in spatial learning and novel object recognition are observed. They precede the loss of motor function indicating that they are not confounded.
  Memory (probe trial performance) is not affected at this age.
• 20 weeks: deficits in cognitive function; depending on the task assessed, these déficits could  be significantly influenced by profound motor déficits present at this age
• 30 weeks: reduced exploring time in the novel object recognition test (reduced cognitive function) and longer immobility periods in the tail suspension test (depressive-like state). These deficits may be affected by the severe motor dysfunctions present at this age.

Electrophysiology

• Alterations in intrinsic and synaptic properties of dopamine neurons occur before and concomitant with motor impairment. Notably disruption of pacemaker firing regularity and reduced ion channel conductance associated with firing is observed.
  Smaller D2 dopamine receptor-mediated outward current

Neuroinflammation

• Not reported