Mouse: En1-/+ Swiss/OF1 background
Mice with a heterozygous disruption of the engrailed 1 (En1) gene En1+/- in an En2 wild-type (En2+/+) context.
Corresponding human genotype: Evidence indicate that polymorphism in the En1 gene is a susceptibility factors for developing PD.
Target gene: Engrailed 1 (En1)
- 3-4 weeks: no loss of TH-positive neurons is observed in the SN
- 4-24 weeks: stable reduction of TH-positive terminals (19-26%) and DAT expression (22-50%) is observed in the striatum.
Presence of spheroid dystrophic terminals are detected in the striatum that progressively increase from PD 8 to 24 weeks of age.
- 8-48 weeks: progressive loss of TH-positive dopaminergic neurons in the SN reaching 38% at 24 weeks with no further loss observed at 48 weeks.
A loss of 23% is detected in the VTA at 48 weeks.
- 6-8 weeks: the unilateral infusion of purified En2 protein can reduce the loss of TH-positive neurons in the ipsilateral SN
- 4 weeks: reduction of dopamine levels (27%) are observed in the striatum with increased ratio of dopamine metabolites to dopamine concentration.
- 24 weeks: reduction of dopamine levels (46%) are observed in the striatum
- 55 weeks: decrease in dopamine content is observed in the striatum (38%) with an increase of dopamine turnover (23%).
No changes in striatal 5-HT levels are detected.
- Chronoamperometric recording indicates that KCl-induced dopamine release and reuptake are significantly reduced in the dorsal striatum of En1+/- mice at 16 weeks of age compared to wild type
- Not reported
- 24 weeks: reduction in the distance traveled is observed in the open field test as well as a reduction in the number of rearing during locomotor activities. Amphetamine injection (2 mg/kg) increases activity in En1+/- but not in wild type mice.
Response to dopaminergic treatment
- not reported
Non motor Behaviours
- Anxiety: wild type and heterozygous mice spend the same amount of time in the central area of the open field and show no differences in the elevated plus maze test indicative of an absence of anxiety.
- Depression: En1+/- mice show greater immobility time in the forced Swimming test compared to wild type mice at 24 weeks. This different can not be accounted for by reduced motor activity and is therefore indicative of an increased depressive-like behavior.
- Anhedonia: En1+/-mice display an anhedonia-like behavior in the Preference Index for Saccharine test at 24 weeks of age. The behavior is saccharine concentration-dependent.
- Adipsic behaviour: En1+/- mice consumed less fluid compared to wild type animals (24 weeks).
- Social interaction: reduction of social activity is observed in heterozygous mice; this reduction is independent from the hypoactivity.
- 16 weeks: chronoamperonometric recordings indicate that neurotransmission is functionally impaired in the dorsal striatum of En1+/-
- Not reported